Littérature scientifique sur le sujet « Tyrosine Kinase Inhibitors (TKIs) »
Créez une référence correcte selon les styles APA, MLA, Chicago, Harvard et plusieurs autres
Consultez les listes thématiques d’articles de revues, de livres, de thèses, de rapports de conférences et d’autres sources académiques sur le sujet « Tyrosine Kinase Inhibitors (TKIs) ».
À côté de chaque source dans la liste de références il y a un bouton « Ajouter à la bibliographie ». Cliquez sur ce bouton, et nous générerons automatiquement la référence bibliographique pour la source choisie selon votre style de citation préféré : APA, MLA, Harvard, Vancouver, Chicago, etc.
Vous pouvez aussi télécharger le texte intégral de la publication scolaire au format pdf et consulter son résumé en ligne lorsque ces informations sont inclues dans les métadonnées.
Articles de revues sur le sujet "Tyrosine Kinase Inhibitors (TKIs)"
1
Deininger, Michael. "Targeting Tyrosine Kinase Receptors." Blood 122, no. 21 (2013): SCI—25—SCI—25. http://dx.doi.org/10.1182/blood.v122.21.sci-25.sci-25.
Texte intégralRésumé :
Abstract Protein tyrosine kinases (PTKs) regulate cell growth and other key functions. Constitutive PTK activation by somatic mutations, overexpression, or abnormal upstream signaling is characteristic of many cancers, including hematologic malignancies, providing a rationale for therapeutically targeting PTKs with small molecules. Imatinib, an ATP-competitive inhibitor of BCR-ABL1, the PTK causal to chronic myeloid leukemia (CML), established a paradigm for tyrosine kinase inhibitors (TKIs) as cancer therapeutics. Although a relatively weak inhibitor, imatinib is effective in most patients with chronic phase CML (CML-CP), while responses are transient in blastic phase (CML-BP). Point mutations in the BCR-ABL1 kinase domain have emerged as a major mechanism of drug resistance. The more potent second-generation TKIs – dasatinib, nilotinib, and bosutinib – induce deeper and faster responses and are active against many imatinib-resistant mutants, with the exception of T315I in the gatekeeper position of the catalytic site. This problem was addressed with ponatinib, a third-generation TKI covering all single BCR-ABL1 mutants, including T315I. Ponatinib has excellent clinical activity in CML-CP patients who failed other TKIs, while responses in CML-BP are short-lived. Some patients fail ponatinib due to BCR-ABL1 compound mutations, suggesting even third-generation TKIs cannot completely prevent mutational escape by the disease-initiating kinase. Another unsolved problem is that TKIs fail to efficiently target CML stem cells, leading to recurrence of active leukemia upon discontinuation. Despite these shortcomings, TKIs have completely changed the face of CML. Unfortunately, repeating this success in other hematologic malignancies has been challenging, likely reflecting differences in disease biology as much as suboptimal design of early compounds. CML-CP represents one extreme of the spectrum, where a single genetic lesion is sufficient to produce the phenotype and the hierarchy of hematopoietic differentiation is maintained. The situation is different in acute myeloid leukemia (AML) with activating FLT3 mutations. Not only these AML cases have mutations in other genes, they typically acquire FLT3 mutations late during disease evolution, implying that the disease-initiating clone will be impervious to FLT3 inhibition. Progress has been made through successive development of more potent TKIs with improved pharmacology, leading to quizartinib. It is clear, however, that FLT3 inhibitors cannot be used as single agents if there is a curative intent and the same may be true for JAK2 inhibitors in myelofibrosis. The first approved JAK2 inhibitor, ruxolitinib, dramatically improves symptoms, but has yet to demonstrate a significant impact on the malignant clone and is certainly not curative. It remains to be seen whether this reflects the fact that JAK2 activation is not the disease–initiating event, lack of inhibitor specificity towards the mutant JAK2 kinase, or other undesirable off-target effects that may be overcome with improved drugs. A completely new chapter was opened with ibrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase (BTK), for the treatment of chronic lymphocytic leukemia (CLL). BTK is essential for signal transduction from the B-cell receptor (BCR). No activating mutations in BTK have been identified in lymphoma or CLL, but constitutive BCR signaling is critical to CLL cell survival in the microenvironment. Early studies show excellent clinical activity in patients with advanced CLL, although many responses are incomplete; much like the imatinib responses in late CML-CP. Ibrutinib may have a similarly profound effect upon CLL as imatinib on CML, but perhaps also similar limitations, such as the inability to eradicate residual leukemia; this of course needs to be tested in frontline studies. TKIs have had a significant albeit uneven impact upon treatment paradigms in hematologic malignancies. Future progress will involve optimizing compounds in terms of potency, selectivity, and pharmacokinetics. Allosteric inhibitors may add to the armamentarium. From the target perspective, it is likely that most activated kinase alleles have been discovered and the focus should shift to identification of disease-critical unmutated kinases. Lastly, identifying synthetically lethal inhibitor combinations will be critical to fully exploit the potential of TKI therapy. Disclosures: Deininger: BMS: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; ARIAD: Consultancy, Membership on an entity’s Board of Directors or advisory committees; NOVARTIS: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; CELGENE: Research Funding; GENZYME: Research Funding; INCYTE: Consultancy, Membership on an entity’s Board of Directors or advisory committees; GILEAD: Research Funding.
2
Abruzzese, Elisabetta, Malgorzata Monika Trawinska, Paolo De Fabritiis, and Alessio Pio Perrotti. "TYROSINE KINASE INHIBITORS AND PREGNANCY." Mediterranean Journal of Hematology and Infectious Diseases 6, no. 1 (2014): e2014028. http://dx.doi.org/10.4084/mjhid.2014.028.
Texte intégralRésumé :
The management of patients with chronic myeloid leukemia (CML) during pregnancy has became recently a matter of continuous debate. The introduction of the Tyrosine Kinase Inhibitors (TKIs) in clinical practice has dramatically changed the prognosis of CML patients. Patients diagnosed in chronic phase can reasonably expect many years of excellent disease control and good quality of life, as well as a normal life expectancy. This fact has come the necessity to address issues relating to fertility and pregnancy. Physicians are not infrequently being asked for advice regarding the need for, and or the appropriateness of, stopping treatment in order to conceive. In this report we will review the data published in terms of fertility, conception, pregnancy, pregnancy outcome and illness control for all the approved TKIs, as well as suggest how to manage a planned and/or unplanned pregnancy.
3
Weatherald, Jason, Louise Bondeelle, Marie-Camille Chaumais, et al. "Pulmonary complications of Bcr-Abl tyrosine kinase inhibitors." European Respiratory Journal 56, no. 4 (2020): 2000279. http://dx.doi.org/10.1183/13993003.00279-2020.
Texte intégralRésumé :
Tyrosine kinase inhibitors (TKIs) targeting the Bcr-Abl oncoprotein revolutionised the treatment of chronic myelogenous leukaemia. Following the success of imatinib, second- and third-generation molecules were developed. Different profiles of kinase inhibition and off-target effects vary between TKIs, which leads to a broad spectrum of potential toxicities.Pulmonary complications are most frequently observed with dasatinib but all other Bcr-Abl TKIs have been implicated. Pleural effusions are the most frequent pulmonary complication of TKIs, usually associated with dasatinib and bosutinib. Pulmonary arterial hypertension is an uncommon but serious complication of dasatinib, which is often reversible upon discontinuation. Bosutinib and ponatinib have also been associated with pulmonary arterial hypertension, while imatinib has not. Rarely, interstitial lung disease has been associated with TKIs, predominantly with imatinib.Mechanistically, dasatinib affects maintenance of normal pulmonary endothelial integrity by generating mitochondrial oxidative stress, inducing endothelial apoptosis and impairing vascular permeability in a dose-dependent manner. The mechanisms underlying other TKI-related complications are largely unknown. Awareness and early diagnosis of the pulmonary complications of Bcr-Abl TKIs is essential given their seriousness, potential reversibility, and impact on future treatment options for the underlying chronic myelogenous leukaemia.
4
Rajeswari, Aruna, and Balaprakash Bhavani. "The Role of Tyrosine Kinases in Cancer: Signal Transduction Mechanisms and Therapeutic Targets." International Journal of Health Sciences and Research 14, no. 9 (2024): 320–36. http://dx.doi.org/10.52403/ijhsr.20240942.
Texte intégralRésumé :
Tyrosine kinases are key mediators in cellular signaling, governing essential processes such as growth, differentiation, metabolism, and apoptosis. In cancer, these kinases often become dysregulated due to mutations, overexpression, or autocrine-paracrine signaling, leading to uncontrolled cell proliferation and tumor development. Receptor tyrosine kinases (RTKs), a prominent subset, are frequently implicated in cancer, with many tumors exhibiting dependency on aberrant RTK signaling. This dependency has made RTKs a major focus for targeted cancer therapies, particularly through the development of small molecule tyrosine kinase inhibitors (TKIs). Despite the initial success of these inhibitors in clinical settings, the emergence of resistance remains a significant hurdle, often leading to relapse. Advances in technology are now facilitating the identification of novel RTK inhibitors, aiming to overcome resistance and improve therapeutic outcomes. This abstract highlight the importance of understanding the signal transduction mechanisms of tyrosine kinases and emphasizes their potential as therapeutic targets in the ongoing battle against cancer. Key words: Tyrosine kinase, Cancer, signaling, Inhibitor, drugs
5
Hu, Chunqi, and Xiaowu Dong. "Cysteine-targeted Irreversible Inhibitors of Tyrosine Kinases and Key Interactions." Current Medicinal Chemistry 26, no. 31 (2019): 5811–24. http://dx.doi.org/10.2174/0929867325666180713124223.
Texte intégralRésumé :
Tyrosine kinases are a subgroup of a large class of protein kinases that transfer phosphate groups from ATP to various amino acid residues. By phosphorylating the tyrosine residues, the tyrosine kinases are responsible for the activation of various proteins through signal transduction cascades, which serves as a ubiquitous mechanism of cell signaling. The frequent success of many tyrosine kinase inhibitors (TKIs) in clinical success and diseasecausing mutations in protein kinases suggests that a large number of kinases may represent therapeutically relevant targets. To date, most of the clinical and preclinical TKIs are ATPcompetitive non-covalent inhibitors, which achieve their selectivity by recognizing the unique features of specific protein kinases. Of growing interest now in the scientific community is the development of irreversible inhibitors that form covalent bonds with cysteines or other nucleophilic residues in the ATP binding pocket. Irreversible TKIs have many potential advantages including prolonged pharmacodynamics, reasonable compound design suitability, high potency, and the ability to validate pharmacological specificity by mutations in reactive cysteine residues. Here, we review recent efforts to develop cysteine-targeting irreversible TKIs and to discuss their patterns of configuration that identify adenosine triphosphate binding pockets and their biological activities.
6
Jacobs, Chaja F., Eric Eldering, and Arnon P. Kater. "Kinase inhibitors developed for treatment of hematologic malignancies: implications for immune modulation in COVID-19." Blood Advances 5, no. 3 (2021): 913–25. http://dx.doi.org/10.1182/bloodadvances.2020003768.
Texte intégralRésumé :
Abstract Tyrosine kinase inhibitors (TKIs) are used to target dysregulated signaling pathways in virtually all hematologic malignancies. Many of the targeted signaling pathways are also essential in nonmalignant immune cells. The current coronavirus severe acute respiratory syndrome coronavirus 2 pandemic catalyzed clinical exploration of TKIs in the treatment of the various stages of COVID-19, which are characterized by distinct immune-related complications. Most of the reported effects of TKIs on immune regulation have been explored in vitro, with different class-specific drugs having nonoverlapping target affinities. Moreover, many of the reported in vivo effects are based on artificial animal models or on observations made in symptomatic patients with a hematologic malignancy who often already suffer from disturbed immune regulation. Based on in vitro and clinical observations, we attempt to decipher the impact of the main TKIs approved or in late-stage development for the treatment of hematological malignancies, including inhibitors of Bruton’s tyrosine kinase, spleen tyrosine kinase, BCR-Abl, phosphatidylinositol 3-kinase/ mammalian target of rapamycin, JAK/STAT, and FMS-like tyrosine kinase 3, to provide a rationale for how such inhibitors could modify clinical courses of diseases, such as COVID-19.
7
Moradpour, Zahra, and Leila Barghi. "Novel Approaches for Efficient Delivery of Tyrosine Kinase Inhibitors." Journal of Pharmacy & Pharmaceutical Sciences 22 (January 13, 2019): 37–48. http://dx.doi.org/10.18433/jpps29891.
Texte intégralRésumé :
Epidermal growth factor receptors (EGFRs) have potential to be considered as therapeutic target for cancer treatment especially in cancer patients with overexpression of EGFR. Cetuximab as a first monoclonal antibody and Imatinib as the first small molecule tyrosine kinase inhibitor (SMTKI) were approved by FDA in 1998 and 2001. About 28 SMTKIs have been approved until 2015 and a large number of compound with kinase inhibitory activity are at the different phases of clinical trials. Although Kinase inhibitors target specific intracellular pathways, their tissue or cellular distribution are not specific. So treatment with these drugs causes serious dose dependent side effects. Targeted delivery of kinase inhibitors via dendrimers, polymeric nanoparticles, magnetic nanoparticles and lipid based delivery systems such as liposomes, solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) can lead to reduction of side effects and improving therapeutic efficacy of the drugs in the target organs. Furthermore formulation of these drugs is challenged by their physicochemical properties such as solubility and dissolution rate. The main approaches in order to increase dissolution rate, are particle size reduction, self-emulsification, cyclodextrin complexation, crystal modification and amorphous solid dispersion. Synergistic therapeutic effect, decreased side effects and drug resistant, reduced cost and increased patient compliance are the advantages associated with using combination therapy especially in the treatment of cancer. Combination of TKIs with chemotherapeutic agents or biopharmaceuticals such as monoclonal antibodies and oligonucleotides and also combination of two TKIs within one formulation is possible by new targeting delivery systems. This article reviews the recent advances in the design and development of delivery systems for TKIs.
8
Aldaz, Paula, and Imanol Arozarena. "Tyrosine Kinase Inhibitors in Adult Glioblastoma: An (Un)Closed Chapter?" Cancers 13, no. 22 (2021): 5799. http://dx.doi.org/10.3390/cancers13225799.
Texte intégralRésumé :
Glioblastoma (GBM) is the most common and lethal form of malignant brain tumor. GBM patients normally undergo surgery plus adjuvant radiotherapy followed by chemotherapy. Numerous studies into the molecular events driving GBM highlight the central role played by the Epidermal Growth Factor Receptor (EGFR), as well as the Platelet-derived Growth Factor Receptors PDGFRA and PDGFRB in tumor initiation and progression. Despite strong preclinical evidence for the therapeutic potential of tyrosine kinase inhibitors (TKIs) that target EGFR, PDGFRs, and other tyrosine kinases, clinical trials performed during the last 20 years have not led to the desired therapeutic breakthrough for GBM patients. While clinical trials are still ongoing, in the medical community there is the perception of TKIs as a lost opportunity in the fight against GBM. In this article, we review the scientific rationale for the use of TKIs targeting glioma drivers. We critically analyze the potential causes for the failure of TKIs in the treatment of GBM, and we propose alternative approaches to the clinical evaluation of TKIs in GBM patients.
9
Jabbar, Sarah, and Mohammed Mohammed. "An in silico study of new 1-aminoquinoline-2(1H)-one derivatives as tyrosine kinase inhibitors." Turkish Computational and Theoretical Chemistry 9, no. 1 (2024): 63–74. https://doi.org/10.33435/tcandtc.1500969.
Texte intégralRésumé :
The field of oncology has been revolutionized by the discovery and development of targeted therapies for cancer. A study focuses on the development of tyrosine kinase inhibitors (TKIs) as effective targeted therapies. Although TKIs have shown promise in targeting cancer cell signaling pathways, the emergence of resistance poses a significant challenge, necessitating the development of novel and potent inhibitors. Virtual docking simulations, which use molecular docking algorithms and scoring functions, predict how these TKIs bind to the enzyme and assess their binding strength. Preliminary results show that several of the designed TKIs have a strong binding affinity and form key interactions with the target tyrosine kinase. These interactions include hydrogen bonds, hydrophobic interactions, and electrostatic interactions, which are crucial for stabilizing the complex between the TKI and the enzyme. Additionally, the study identifies specific amino acid residues within the tyrosine kinase binding site that enhance the binding affinity of the TKIs. This detailed information is valuable for further optimizing TKI design and developing more effective inhibitors with improved binding properties.
10
Roy, Bhaskar, Avash Das, Kumar Ashish, et al. "Neuropathy with vascular endothelial growth factor receptor tyrosine kinase inhibitors." Neurology 93, no. 2 (2019): e143-e148. http://dx.doi.org/10.1212/wnl.0000000000007743.
Texte intégralRésumé :
ObjectiveTo explore the association of peripheral neuropathy with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) use in patients with cancer.MethodsPublished data search up to November 2018 reporting peripheral neuropathy in patients with cancer treated with VEGFR-TKIs was performed. The primary outcome was presence of peripheral neuropathy at the end of the trial. Random-effects meta-analysis was performed to estimate relative risk (RR) of individual treatment.ResultsThirty randomized clinical trials (RCTs) including 12,490 patients with cancer were included in this analysis. Eight studies compared VEGFR-TKIs with placebo and the remaining studies compared VEGFR-TKIs with the standard chemotherapeutic regimen. When compared against placebo, VEGFR-TKIs were associated with a higher risk of peripheral neuropathy (RR 1.76; 95% confidence interval [CI] 1.13–2.75, p = 0.01). Similarly, a stronger association was noted for sensory neuropathy with VEGFR-TKIs monotherapy (RR 1.61; 95% CI 1.09–2.37, p = 0.02). Risk of peripheral neuropathy with VEGFR-TKIs was higher even when they were compared against control (either placebo or standard chemotherapeutic agents) (RR 1.08; 95% CI 1.01–1.15, p = 0.03). High-grade neuropathy (RR 1.28; 95% CI 1.06–1.54, p <0.01) and high-grade sensory neuropathy (RR 1.38; 95% CI 1.09–1.74, p < 0.01) were noted more frequently with VEGFR-TKIs treatment compared against control.ConclusionsVEGFR-TKIs therapy appeared to be associated with an increased risk of neuropathy.
Thèses sur le sujet "Tyrosine Kinase Inhibitors (TKIs)"
1
Recondo, Gonzalo. "Resistance Mechanisms to ALK Tyrosine Kinase Inhibitors (TKIs) in NSCLC." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS248/document.
Texte intégralRésumé :
Les analyses moléculaires et la classification des adénocarcinomes bronchiques ont conduit au développement de thérapies ciblées sélectives visant à améliorer le contrôle de la maladie et la survie des patients. ALK (anaplastic lymphoma kinase) est un récepteur tyrosine kinase de la famille des récepteurs de l'insuline. Des réarrangements chromosomiques impliquant le domaine kinase d’ALK sont présents dans environ 3 à 6% des patients atteints d'un adénocarcinome bronchique. La protéine de fusion provoque une activation du domaine kinase de manière constitutive et indépendante du ligand. Lorlatinib est un inhibiteur d’ALK de troisième génération avec une efficacité et une sélectivité optimale, ainsi qu’une pénétration élevée vers le système nerveux central. Lorlatinib peut vaincre la résistance induite par plus de 16 mutations secondaires dans le domaine kinase d’ALK acquises lors de la progression aux ALK TKI de première et deuxième générations. Le traitement par lorlatinib est donc efficace chez les patients préalablement traités par un ALK TKI de première ou deuxième génération, et est actuellement approuvé pour cette indication. Le spectre complet de mécanismes de résistance au lorlatinib chez les patients reste à élucider. Il a récemment été rapporté que l'acquisition séquentielle de deux mutations ou plus dans le domaine kinase, également appelées mutations composées, est responsable de la progression de la maladie chez environ 35% des patients traités par le lorlatinib, principalement en altérant sa liaison au domaine kinase d’ALK. Cependant, l’effet de ces mutations sur la sensibilité aux différents inhibiteurs d’ALK peut varier, et les autres mécanismes de résistance survenant chez la plupart des patients restent inconnus. Mon travail de thèse avait pour but d’explorer la résistance au lorlatinib chez des patients atteints d'un cancer du poumon ALK réarrangé par la mise en œuvre de biopsies spatiales et temporelles et le développement de modèles dérivés de patients. Dans le cadre de l’étude institutionnelle MATCH-R (NCT02517892), nous avons effectué un séquençage à haut débit de l’exome, de l’ARN et ciblé, ainsi qu’un séquençage des ctDNA afin d’identifier les mécanismes de résistance. Nous avons établi des lignées cellulaires dérivées de patients et caractérisé de nouveaux mécanismes de résistance et identifiés de nouvelles stratégies thérapeutiques in vitro et in vivo. Nous avons identifié trois mécanismes de résistance chez quatre patients avec des biopsies appariées. Nous avons étudié l'induction de la transition épithélio-mésenchymateuse (EMT) par l'activation de SRC dans une lignée cellulaire, dérivée d’un patient, exposée au lorlatinib. Les cellules mésenchymateuses étaient sensibles à l’inhibition combinée de SRC et d'ALK, montrant que même en présence d'un phénotype agressif, des stratégies de combinaison peuvent surmonter la résistance aux ALK TKI. Nous avons identifié deux nouvelles mutations composées du domaine kinase d’ALK, F1174L / G1202R, C1156Y / G1269A survenues chez deux patients traités par le lorlatinib. Nous avons développé des modèles de cellules Ba / F3 exprimant les mutations simples et composées pour étudier leur effet sur la résistance au lorlatinib. Enfin, nous avons caractérisé un nouveau mécanisme de résistance provoqué par la perte de fonction de NF2 au moment de la progression du lorlatinib par l’utilisation de PDX et de lignées cellulaires dérivées de patients, et par CRISPR / CAS9 knock-out de NF2. Nous avons constaté que l'activation de mTOR par la perte de fonction de NF2 provoquait la résistance au lorlatinib et qu'elle pouvait être surmontée par le traitement avec des inhibiteurs de mTOR.Cette étude montre que les mécanismes de résistance au lorlatinib sont plus divers et complexes que prévu. Nos résultats démontrent également comment les études longitudinales de la dynamique tumorale permettent de déchiffrer la résistance aux TKI et d'identifier des stratégies thérapeutiques<br>The molecular study and classification of lung adenocarcinomas has led to the development of selective targeted therapies aiming to improve disease control and survival in patients. The anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor from the insulin tyrosine kinase receptor family, with a physiologic role in neural development. Gene rearrangements involving the ALK kinase domain occur in ~3-6% of patients with lung adenocarcinoma. The fusion protein dimerizes leading to transactivation of the ALK kinase domain in a ligand-independent and constitutive manner. Lorlatinib is a third generation ALK inhibitor with high potency and selectivity for this kinase in vitro and in vivo, and elevated penetrance in the central nervous system. Lorlatinib can overcome resistance mediated by over 16 secondary kinase domain mutations occurring in 13 residues upon progression to first - and second - generation ALK TKI. In addition, treatment with lorlatinib is effective for patients who have been previously treated with a first and a second generation or a second generation ALK TKI upfront and is currently approved for this indication. The full spectrum of biological mechanisms driving lorlatinib resistance in patients remains to be elucidated. It has been recently reported that the sequential acquisition of two or more mutations in the kinase domain, also referred as compound mutations, is responsible for disease progression in about 35% of patients treated with lorlatinib, mainly by impairing its binding to the ALK kinase domain. However, the effect of these compound mutations on the sensitivity to the repertoire of ALK inhibitors can vary, and other resistance mechanisms occurring in most patients are unknown. My PhD thesis aimed at exploring resistance to lorlatinib in patients with ALK-rearranged lung cancer through spatial and temporal tumor biopsies and development of patient-derived models. Within the institutional MATCH-R study (NCT02517892), we performed high-throughput whole exome, RNA and targeted next-generation sequencing, together with plasma sequencing to identify putative genomic and bypass mechanisms of resistance. We developed patient-derived cell lines and characterized novel mechanisms of resistance and personalized treatment strategies in vitro and in vivo. We characterized three mechanisms of resistance in four patients with paired biopsies. We studied the induction of epithelial-mesenchymal transition (EMT) by SRC activation in a patient-derived cell line exposed to lorlatinib. Mesenchymal cells were sensitive to combined SRC and ALK co-inhibition, showing that even in the presence of an aggressive and challenging phenotype, combination strategies can overcome ALK resistance. We identified two novel ALK kinase domain compound mutations, F1174L/G1202R, C1156Y/G1269A, occurring in two patients treated with lorlatinib. We developed Ba/F3 cell models harboring single and compound mutations to study the differential effect of these mutations on lorlatinib resistance. Finally, we characterized a novel mechanism of resistance caused by NF2 loss of function at the time of lorlatinib progression through the development of patients derived PDX and cell lines, and in vitro validation of NF2 knock-out with CRISPR/CAS9 gene editing. Downstream activation of mTOR was found to drive lorlatinib resistance by NF2 loss of function and was overcome by providing treatment with mTOR inhibitors.This study shows that mechanisms of resistance to lorlatinib are more diverse and complex than anticipated. Our findings also emphasize how longitudinal studies of tumor dynamics allow deciphering TKI resistance and identifying reversing strategies
2
Grassi, Susanna. "BCR/ABL1-independent markers of resistance in patients affected by chronic myeloid leukemia (CML) receiving tyrosine kinase inhibitors (TKIs)." Doctoral thesis, Università di Siena, 2019. http://hdl.handle.net/11365/1073133.
Texte intégralRésumé :
Chronic Myeloid Leukemia (CML) is a chronic myeloproliferative neoplasm derived from the neoplastic transformation of the pluripotent stem cell characterized by the reciprocal translocation between chromosome 9 (9q) and 22 (22q) t (9; 22) (q34; q11), which leads to the formation of a new BCR-ABL1 gene that causes expansion of the pathological clone. The introduction of tyrosine kinase inhibitor drugs (TKIs) has revolutionized the treatment of this neoplasm. However, about a third of patients have to suspend treatment for resistance or intolerance to TKIs. The aim of our study was to identify the factors that affect the efficacy and toxicity of TKIs, evaluating biological mechanisms that cause BCR/ABL1-independent resistance in the leukemic cell, in order to find new markers of prognosis and for a target therapy. The study was divided in several part: 1) to evaluate the influence of polymorphisms (SNPs) of membrane transporters hOCT1, ABCB1, ABCG2, SLCO1B3 on the pharmacokinetics of Imatinib and Nilotinib; 2) to evaluate if aspects of epigenetics, such as the expression of the Polycomb group genes (PcGs), can correlate with the response to Imatinib; 3) evaluation of BMI1 as marker of LSCs; 4) the study of the gene expression profile of pathways of PcGs, JAK/STAT and Wnt/b-catenin, involved in the resistance and progression of the disease; 5) identification of CML-related proteins in a different compartment from peripheral blood or bone marrow (salivary proteomic). From the data collected on patients enrolled in the TIKlet protocol, we have shown that the polymorphism of hOCT1c.480C>G significantly influences the clearance of Imatinib. About Nilotinib, thanks to a pharmacokinetic model that we have developed, it was possible to highlight how the elimination rate of nilotinib was influenced by the polymorphism ABCB1 c.2677G>T/A. Furthermore, SLCO1B3 c.334T>G is significantly associated with the bioavailability of Nilotinib. At the same time, patients with the SCLO1B3 c.521C allele will take longer to achieve the complete cytogenetic response or MR3. In addition, we demonstrated in our patients the impact of the PcGs, epigenetic repressors involved in the progression of CML and resistance to therapy. We measured the expression of 8 PcGs before and after three months of treatment with Imatinib from bone marrow samples of 30 patients. The expression of BMI1, PHC3, CBX6 and CBX7 was significantly increased during treatment with TKI; in particular, we shown that the increase in BMI1 had a negative impact on the prognosis, even in the subgroup of patients with unfavorable hOCT1. BMI1 is responsible for the resistance to the TKIs in a BCR-ABL1-independent way, even if is unknown where BMI1 in CML is expressed (in progenitors or more mature cells). We decided, therefore, to evaluate if and where the BMI1 protein is located, focusing on the CD34+/CD38-/CD26+ CML progenitors. We measured, by flow cytometry, the proportion of CD34+/CD26+ cells in bone marrow of 20 CML patients, at diagnosis and during treatment with imatinib. After that the bone marrow blood smears were stained with antibodies anti-CD26, BCR-ABL1, and BMI1. These smears were observed by a confocal laser microscope and we showed that the BMI1 protein was co-expressed in the cytoplasm of the CD26+ precursors. In parallel, we performed the expression analysis of 255 genes, related to the WNT, JAK/STAT and PcGs pathways. We measured genes de- regulation after 6 months of therapy in 11 CML patients. In order to find possible correlations with quality of response to treatment and event-free-survival (EFS). These results were then re-analyzed by the principal component method (PCA) for tempting to better cluster resistant cases. WNT was the most responsible pathway for the TKIs resistance. Indeed, 100% of patients with a “low” up-regulation of this pathway achieved an optimal response versus 33% of those who showed a “high” gene over-expression (p=0.016). Analogously, the 24-months EFS resulted significantly influenced by the degree of up-regulation of the WNT signaling: all patients with a “low” up-regulation were event- free versus 33% of those who presented a “high” gene expression (p=0.05). In particular, the PCA analysis confirmed the role of WNT pathway and showed that the most significantly up-regulated genes with negative prognostic value were DKK, WNT6, WISP1 and FZD8. Moreover, we focused on the study of salivary proteomic, and although our study was preliminary, the analysis of proteomic expression identified proteins related to the bone marrow niche, differentiation and stemness. In particular, there was a significantly different proteomic profile of resistant in comparison to the sensitive patients. This data could allow the assessment of the salivary compartment as an alternative to those already used for the monitoring of patients with CML. In conclusion, our results sustain the need of a wide and multitasking approach in order to understand the resistance mechanisms in CML. This study allowed us to demonstrate how pharmacokinetic and pharmacogenomic aspects can be important in the management of the patient with CML, for the choice of the type of drug to be used in the first line to reduce toxicity, that negative impacts on the quality of life, to promote adherence to treatment and prevent the loss of response. TKIs act on intracellular pathways other than BCR-ABL1 and, even if in a small cohort of CML patients, we found a significant de- regulation of WNT pathway and we demonstrated that its activation could affect the sensitivity to TKIs and the clinical outcome. Once translated into the clinical context, our results would suggest the combination of the WNT/β-catenin with TKIs. Then, if BMI1 is a marker of stemness, also combination with TKIs and BMI1 inhibitors could be a promising way to overcome resistance in CML patients.
3
SARONNI, DAVIDE. "TYROSINE KINASE INHIBITORS IN NEUROENDOCRINE TUMORS: FROM IN VITRO TO ZEBRAFISH MODEL." Doctoral thesis, Università degli Studi di Milano, 2022. http://hdl.handle.net/2434/917967.
Texte intégralRésumé :
(1) Background: Neuroendocrine neoplasms (NENs) are a group of tumors that arise from neuroendocrine cells throughout the body, with the lungs and gastrointestinal tract being the most common sites of origin. In patients with NENs and distant metastases, surgery is generally not curative. Although well-differentiated and low-grade NENs, classified as neuroendocrine tumors (NETs), are usually less aggressive than poorly-differentiated NENs, they can develop distant metastases in about 15% of cases. These patients require chronic medical management. However, the clinical efficacy of these treatments is limited by the low objective response rate, due to the occurrence of tumor resistance and the high biological heterogeneity of these neoplasms.
(2) Research problem: We addressed this study on two rare NETs: lung neuroendocrine tumors (LNETs) and medullary thyroid carcinoma (MTC). LNETs represent about 2% of lung tumors, while MTCs are rare thyroid tumors caused by mutations in the RET proto-oncogene. Both NETs are well-differentiated neoplasms and are known to be highly vascularized. Therefore, they represent a potential target for tyrosine kinase inhibitors (TKIs) selective for receptors involved in angiogenesis. The aim of this project was to evaluate the antitumor activity of several new TKIs both in vitro, using LNETs (NCI-H727, UMC-11 and NCI-H835) and MTC (TT and MZ-CRC-1) cell lines, and in vivo, adopting a novel zebrafish xenograft model to study angiogenesis. In LNETs we tested: sulfatinib, a small molecule that inhibits the Vascular Endothelial Growth Factor Receptor (VEGFR) 1, 2, and 3, and the Fibroblast Growth Factor Receptor type 1 (FGFR1); cabozantinib, a multi-target inhibitor selective for VEGFR2, c-Met, Kit, Axl and Flt3; and axitinib, a multi-target TKI of VEGFR1, 2, 3 and Platelet-Derived Growth Factor Receptor-beta (PDGFRβ). In MTC we tested: sulfatinib; SPP86, a RET-specific inhibitor; and SU5402, an inhibitor of the FGFR1 and VEGFR2.
(3) Methodology: In LNETs and MTC cells the effects of selected TKIs have been evaluated in vitro through: MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assays, for assessing cell viability; flow-cytometer analysis, for the evaluation of cell cycle and apoptosis; and wound-healing assay, to study cell migration. In vivo we took advantage of the transgenic zebrafish line of Tg(fli1a:EGFP)y1. Through the xenotransplantation of NET cells in the subperidermal space near the subintestinal vein, we assessed the effects of TKIs on tumor-induced angiogenesis and cancer dissemination.
(4) Key Results: In LNET cell lines we observed a dose-dependent decrease in cell viability after incubation with all TKIs. This effect seems to be related to the perturbation of the cell cycle and induction in apoptosis. In NCI-H727 wound healing assay showed a significant reduction in cell migration only after incubation with cabozantinib. In the zebrafish model, we found a significant reduction of the tumor-induced angiogenesis in implanted LNET cell lines after treatment with all TKIs. Cabozantinib and axitinib were more potent than sulfatinib in inhibition of angiogenesis, while cabozantinib was the most efficient in reducing cell migration from the transplantation site to the tail. In MTC cell lines, sulfatinib, SU5402 and SPP86 showed a decrease in cell viability, confirmed by the significant reduction in S phase cell population. Moreover, sulfatinib and SPP86 showed for both cell lines a significant induction of apoptosis. Sulfatinib and SPP86 inhibited the migration of TT and MZCRC-1 cells, evaluated through the wound healing assay, while SU5402 was able to inhibit migration only in TT cells. In vivo we observed a significant reduction of TT cells-induced angiogenesis in zebrafish embryos after treatment with sulfatinib and SPP86.
(5) Conclusions: Despite sulfatinib resulted the most potent compound in terms of inhibition of LNET cell proliferation, cabozantinib showed in vivo the most effective impact in reducing tumor-induced angiogenesis. Cabozantinib was the only TKI able to inhibit in vivo the dissemination of implanted LNET cells. According to these data, cabozantinib could represent a potential candidate in the therapy of patients with highly vascularized LNET. In MTC cell lines, SPP86 and sulfatinib displayed a similar antitumor activity both in vitro and in vivo, suggesting a good efficacy of specific RET inhibitors (SPP86) with potentially less adverse effects than multitarget TKIs (sulfatinib). In addition, this study showed that the zebrafish model for NETs represents an innovative tool for drug screening with several advantages compared with rodent models: rapidity of procedure, animal immune suppression is not required, lower number of tumor cells for implant and the optical transparency provides a real-time monitoring of cell-stromal interactions and cancer progression in living animals.
4
DAMELE, LAURA. "Effect of tyrosine kinase inhibitors on NK cell and ILC3 dvelopment and function." Doctoral thesis, Università degli studi di Genova, 2020. http://hdl.handle.net/11567/996010.
Texte intégralRésumé :
Tyrosin kinase inhibitors (TKI) sharply improved the prognosis of Chronic Myeloid
Leukemia (CML) and of Philadelphia+ Acute Lymphoblastic Leukemia (Ph+ALL) patients.
However, TKI are not curative because of the development of resistance and
lack of complete molecular remission in the majority of patients. Clinical evidences
would support the notion that patient’s immune system may play a key role in
preventing relapses. In particular, increased proportions of terminally differentiated
CD56+CD16+CD57+ NK cells have been reported to be associated with successful
Imatinib therapy discontinuation or with a deep molecular response in Dasatinib-treated
patients. In view of the potential role of NK cells in immune-response against
CML, it is important to study whether any TKI have an effect on the NK cell
development and identify possible molecular mechanism(s) by which continuous
exposure to in vitro TKI may influence NK cell development and repertoire. To
this end, CD34+ hematopoietic stem cells (HSC) were cultured in the absence or
in the presence of Imatinib, Nilotinib, or Dasatinib. We show that all compounds
exert an inhibitory effect on CD56+ cell recovery. In addition, Dasatinib sharply
skewed the repertoire of CD56+ cell population, leading to an impaired recovery
of CD56+CD117−CD16+CD94/NKG2A+EOMES+ mature cytotoxic NK cells, while
the recovery of CD56+CD117+CD94/NKG2A−RORgt+ IL-22-producing ILC3 was not
affected. This effect appears to involve the Dasatinib–mediated inhibition of Src kinases
and, indirectly, of STAT5-signaling activation in CD34+ cells during first days of culture.
Our studies, reveal a possible mechanism by which Dasatinib may interfere with the
proliferation and maturation of fully competent NK cells, i.e., by targeting signaling
pathways required for differentiation and survival of NK cells but not of ILC3.
5
Kangboonruang, Kitsada. "Neoplastic mast cells from patients with mastocytosis express AXL : effects on proliferation, apoptosis, and resistance to tyrosine kinase inhibitors." Electronic Thesis or Diss., Université Paris Cité, 2024. https://wo.app.u-paris.fr/cgi-bin/WebObjects/TheseWeb.woa/wa/show?t=6722&f=79753.
Texte intégralRésumé :
La mastocytose est une maladie rare et hétérogène, caractérisée par l'accumulation de mastocytes (MC) néoplasiques dans un ou plusieurs organes. L'Organisation Mondiale de la Santé (OMS) a classé la mastocytose en plusieurs variantes, dont la mastocytose cutanée (CM), limitée à la peau, la mastocytose systémique (MS), qui affecte la moelle osseuse et divers organes, ainsi que le sarcome mastocytaire (MCS), une tumeur localisée rare et agressive. La MS est ensuite subdivisée en MS non avancée (comprenant la MS indolente (ISM) et la MS à évolution lente (SSM)) et en MS avancées (AdvSM). L'AdvSM inclut la MS agressive (ASM), la MS associée à une néoplasie hématologique (SM-AHN), et la leucémie des mastocytes (MCL), ces formes étant associées à une espérance de vie significativement réduite. Dans 90 % des cas, les MC néoplasiques présentent une mutation somatique KIT D816V, entraînant une activation constitutive du récepteur de la tyrosine kinase KIT, favorisant ainsi la prolifération, l'activation et la survie des MC, même en l'absence du ligand de KIT. Cependant, la mutation KIT D816V à elle seule n'explique pas totalement l'hétérogénéité clinique de la maladie, ce qui suggère l'implication d'autres facteurs dans le développement et la progression de la mastocytose. De plus, les inhibiteurs de la tyrosine kinase (iTK) ont montré une efficacité limitée, indiquant la dérégulation de mécanismes moléculaires supplémentaires. Nos travaux visent à identifier et caractériser des gènes susceptibles de contribuer à la physiopathologie de la mastocytose, élargissant ainsi nos connaissances au-delà du rôle bien établi des mutations de KIT. Nous avons réalisé le séquençage de formes familiales de mastocytoses. Les exomes de 24 familles ont été réalisés ce qui a permis d'identifier quatre différentes mutations germinales dans le gène AXL de six patients provenant de quatre familles. Ces patients portaient également des mutations somatiques dans le gène KIT et souffraient de diverses formes de mastocytoses caractérisées comme étant : AdvSM (n = 1), ISM (n = 2), et CM ou mastocytome (n = 3). Dans cette étude, je me suis concentré sur le cas d'un patient atteint d'AdvSM, qui porte une mutation germinale AXL L197M ainsi qu'une mutation somatique KIT D816V. Le gène AXL code pour un récepteur à tyrosine kinase appartenant à la famille TAM. Bien qu'AXL n'ait jamais été étudié dans les mastocytes ou la mastocytose, il est impliqué dans de nombreuses tumeurs humaines et dans des mécanismes de résistance aux iTK. Nous avons démontré, pour la première fois, l'expression d'AXL dans les mastocytes néoplasiques de patients atteints de divers sous-types de mastocytose. Les mastocytes primaires n'expriment pas AXL ; cependant, nous avons montré que l'interféron-alpha induit son expression. Cette donnée est cohérente avec les niveaux élevés d'interféron-alpha que nous avons détectés dans le plasma des patients atteints de mastocytose, comparés aux témoins sains. Pour déterminer si AXL est un nouvel acteur dans la mastocytose, nous avons produit des vecteurs lentiviraux exprimant AXL-WT et AXL-L197M et avons transduits des lignées de mastocytes exprimant soit KIT-WT, soit KIT-D816V avec ces vecteurs. Nos résultats révèlent une coopération entre la mutation KIT D816V et les mutations AXL WT et AXL L197M entraînant une augmentation de la prolifération des mastocytes ainsi qu'une résistance à l'apoptose et aux iTK. Ainsi, AXL apparaît comme une nouvelle cible thérapeutique pour la mastocytose, comme cela a déjà été démontré dans de nombreux autres cancers, en complément de KIT<br>Mastocytosis is a rare and heterogenous disorder characterized by the accumulation of neoplastic mast cells (MCs) in one or more organs. The World Health Organization (WHO) have been classified mastocytosis into several variants, including cutaneous mastocytosis (CM), which is confined to the skin, systemic mastocytosis (SM), which affects bone marrow and various organs, and MC sarcoma (MCS), which is rare, localized aggressive MC tumor. SM is subsequently divided into non-advanced SM (including indolent SM (ISM) and smoldering SM (SSM)) and advanced SM (AdvSM). AdvSM includes aggressive SM (ASM), SM with an associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL), which are associated with significantly reduced life expectancy. In 90% of the cases, neoplastic MCs harbor a somatic KIT D816V mutation, leading to constitutive activation of the KIT tyrosine kinase receptor, which promotes MC proliferation, activation, and survival, in the absence of its ligand. However, KIT D816V mutation alone does not fully explain the clinical heterogeneity of the disease, suggesting the involvement of other factors in the pathogenesis and progression of mastocytosis. Moreover, tyrosine kinase inhibitors (TKIs) have shown limited efficacy, indicating that additional molecular mechanisms are involved. Our research aims to identify and characterize genes that may contribute to the pathophysiology of mastocytosis, expanding our knowledge beyond the well-established role of KIT mutations. We performed whole-exome sequencing on 24 families with mastocytosis and identified four germline mutations in the AXL gene in six patients from four families. These patients also carried somatic mutations in the KIT gene and exhibited various forms of mastocytosis, including AdvSM (n = 1), ISM (n = 2), and CM or mastocytoma (n = 3). In this study, I focused on the case of a patient with AdvSM who harbors a germline AXL L197M mutation along with a somatic KIT D816V mutation. AXL encodes for a tyrosine kinase receptor of the TAM family. While AXL has never been studied in mast cells or mastocytosis, it has been implicated in many human malignancies and TKI resistance mechanisms. We demonstrated, for the first time, the expression of AXL in neoplastic mast cells from patients with various subtypes of mastocytosis. Primary mast cells do not express AXL; however, we were able to induce its expression using interferon-alpha. This finding is consistent with the elevated interferon-alpha levels we detected in the plasma of mastocytosis patients compared to healthy controls. To determine whether AXL is a novel player in mastocytosis, we constructed lentiviral vectors expressing AXL-WT and AXL-L197M and transduced them into mast cell lines expressing either KIT-WT or KIT-D816V. Our results demonstrate a synergistic cooperation between the KIT D816V mutation and both the AXL WT and AXL L197M mutations in promoting mast cell proliferation, resistance to apoptosis, and resistance to TKIs. Thus, AXL emerges as a promising therapeutic target for mastocytosis, in addition to KIT, as has been shown in many other cancers
6
Aljohani, Hashim M. B. S. "Signaling Pathways Associated with Gefitinib Resistance in Glioblastoma Multiforme (GBM)." University of Cincinnati / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1406900804.
Texte intégral
7
Tonus, Francesca. "Sintesi e studio di sistemi polieterociclici a potenziale attività biologica." Doctoral thesis, Università degli studi di Padova, 2012. http://hdl.handle.net/11577/3425459.
Texte intégralRésumé :
In the last decade, some progresses have been reached in the cancer treatment, mainly through the approval of novel key drugs based on the targeted therapy. In this respect, tyrosine kinases constitute one of the most relevant class of targets. Tyrosine kinases are key enzymes involved in the intracellular signal transduction and their up-regulation is often associated with cancer onset and progression. The tyrosine kinase inhibitors act mainly as ATP-mimic compounds. Despite the initial relevant clinical successes obtained through kinase inhibitor use, rapid drug resistance phenomena onset have been recently emerged when administering highly selective drugs. Consequently, a major goal in the field of tyrosine kinase inhibitor development is to find compounds able to inhibit more than one enzyme, thus overcoming the drug resistance onset.
The synthesis and the biological evaluation of new potential kinase inhibitors are described in this work. Three different quinazoline analogs have been previously identified by our research group, that share the same 3-aminobiphenyl function condensed at 4-position (Figure 1). These compounds were found to posses higher inhibitory potency against cell proliferation when compared with analogues bearing simple aniline moieties condensed at 4-position.
Thus, starting from these results, four classes of quinazoline compounds have been synthesized. The designed derivatives are characterized by different substituents condensed on the dioxanoquinazoline nucleus (n=2) or by different side chains at the position 6 and 7 to the quinazoline nucleus. The quinazoline scaffolds have been synthesized according to an innovative and useful strategy developed by our research group 1.
All the synthesized compounds have been evaluated for their antiproliferative effects on A431 cells that over-express EGFR. In order to define the mechanism of action of the most active compounds, the irreversibility of the effects on the cell growth as well as the interactions with EGFR have been investigated. The effects on HUVEC proliferation, migration and morphogenesis have also been evaluated to assess the antiangiogenic properties of the derivatives. Finally, the compounds have been tested on a panel of human tumor cell lines and on 7 different purified kinases.<br>Nell’ultimo decennio sono stati fatti molti progressi nell’ambito della terapia antitumorale, soprattutto grazie allo sviluppo della targeted therapy che ha portato all’approvazione di nuovi importanti farmaci. Tra i target di elezione per la targeted therapy particolare rilevanza hanno le tirosinchinasi. Le tirosinchinasi sono enzimi fondamentali nella trasduzione del segnale intracellulare e quando sovra-espresse, come spesso accade nelle cellule tumorali, portano ad una de-regolazione e ad un’aumentata proliferazione cellulare. I farmaci approvati come inibitori tirosinchinasici sono per lo più molecole ad azione ATP-mimetica. Nonostante l’iniziale entusiasmo derivante dalla loro elevata efficacia terapeutica, oggi si riscontrano sempre più frequentemente fenomeni di resistenza che rendono inefficace la somministrazione di questi farmaci. Per cercare di superare questo problema la ricerca si sta impegnando nella scoperta di farmaci che siano multi-target, ovvero inibitori multi-chinasici.
A partire da queste considerazioni il progetto di dottorato è stato dedicato alla sintesi e alla valutazione biologica di nuovi potenziali inibitori tirosinchinasici. Da studi precedentemente effettuati all’interno dei laboratori di ricerca in cui questa tesi è stata svolta, era risultato che la funzionalizzazione con 3-amminobifenile di tre diversi nuclei chinazolinici (figura 1) conferiva una maggior potenza inibitoria nei confronti della proliferazione cellulare rispetto ad altri tipi di sostituenti anilinici.
Sono state quindi progettate e sintetizzate quattro classi di composti che differissero per il sostituente in 4 rispetto al nucleo diossanochinazolinico (n=2) o per i sostituenti in 6 o 7 all’anello chinazolinico.
I nuclei chinazolinici sono stati tutti ottenuti seguendo una metodica generale di sintesi messa a punto e validata nel nostro gruppo di ricerca 1.
Per tutti i composti sintetizzati sono stati valutati gli effetti antiproliferativi sulla linea cellulare A431 che sovra-esprime EGFR 2. Il meccanismo di azione dei composti maggiormente attivi è stato quindi indagato, verificando l’irreversibilità dell’azione e la specificità nei confronti di EGFR. Sono stati valutati anche gli effetti sulla proliferazione, sulla migrazione e sulla morfogenesi di cellule HUVEC allo scopo di indagare l’attività antiangiogenica dei nuovi derivati.
Per avere un quadro più completo dell’attività di questi derivati sono stati, infine, valutati gli effetti antiproliferativi su un ampio pannello di linee cellulari tumorali umane e gli effetti inibitori su 7 diverse tirosinchinasi isolate (sia recettoriali che citoplasmatiche).
8
Russell, Kathy, Marion Slack, Janet Cooley, and Kelly Mathews. "Impact of a Specialty Pharmacy-Based Oral Chemotherapy Adherence Program on Patient Adherence." The University of Arizona, 2016. http://hdl.handle.net/10150/614015.
Texte intégralRésumé :
Class of 2016 Abstract<br>Objectives: Patient medication adherence is a basic requirement for treating chronic myelogenous leukemia (CML) with oral tyrosine kinase inhibitors (TKIs). When imatinib adherence rates are less than 80 or 90 percent, major and complete molecular responses, respectively, do not happen. The purpose of this study was to determine the effect of a real-time medication monitoring (RTMM) reminder system adherence program on the medication possession ratio (MPR).
Methods: This analytic study was a retrospective cohort study and used data extracted from chart reviews for patients who received services from 2011 to 2015. It was approved by the Institutional Review Board. The study consisted of an intervention group and a control group (50 patients each).
MPRs, demographic, descriptive, and categorical variables were summarized using means, standard deviations (SD), and frequencies/percentages.
Results: The study population consisted of adult patients (mean age=62.2, SD=2.7, 50% male) treated by Avella Specialty Pharmacy who received imatinib or nilotinib as treatment for CML, gastrointestinal stromal tumors (GIST), or a similar positive Philadelphia chromosome cancer.
Only 4% of patients in the intervention group had an < 85% MPR, compared to 46% in the control group (p < 0.001).
Conclusions: In those patients who had an MPR of ≥ 85%, the difference between the groups was statistically significant. As past studies have shown, adherence rates greater than 90% have a higher likelihood of a major or complete molecular response and a greatly reduced risk of disease progression.
9
Choi, Ho-ying, and 蔡可盈. "Review of clinical benefits and cost effectiveness of epidermal growthfactor receptor-tyrosine kinase inhibitor (EGFR-TKI) as first linetreatment for patients with advanced non-small cell lung cancer(NSCLC)." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B46935320.
Texte intégral
10
Mazed, Fetta. "Etude des mécanismes de résistance aux inhibiteurs de FLT3 dans les leucémies aigues myéloïdes." Thesis, Sorbonne Paris Cité, 2019. http://www.theses.fr/2019USPCC089.
Texte intégralRésumé :
Les leucémies aiguës myéloïdes (LAM) constituent un groupe hétérogène d’hémopathies malignes résultant de la prolifération clonale d’un progéniteur myéloïde bloqué dans sa différenciation. De pronostic globalement défavorable, dépend de l’âge et de facteurs cytogénétiques et moléculaires. La mutation du gène FLT3 de type duplication en tandem du domaine juxta-membranaire (ITD : internal tandem duplication) est détectée dans 30% des échantillons de LAM, corrèle à une fréquence accrue de rechutes et à un pronostic défavorable. La mutation ITD conduit à une activation dérégulée et constitutive de récepteur FLT3, induisant une addiction oncogénique des cellules leucémiques aux voies de signalisation en aval, désignant FLT3 comme cible thérapeutique pertinente dans les LAM. Ainsi, de nombreux inhibiteurs de tyrosine kinase (ITK) ciblant FLT3 ont été développés, certains ayant une efficacité significative en monothérapie et améliorant la survie des patients ayant une mutation FLT3-ITD en association aux traitements conventionnels. Néanmoins, la plupart des patients traités en monothérapie, et une proportion importante de ceux traités en association rechutent en raison de mécanismes de résistance développés par la cellule pour échapper à l’action des ITK. L’étude de ces mécanismes est un enjeu essentiel afin d’améliorer l’efficacité des traitements dans les LAM FLT3-ITD. C’est cette thématique que j’ai souhaité aborder au cours de ma thèse. Nous avons tout d’abord, mis en évidence par des approches transcriptomiques et protéomiques une nouvelle cible de PIM2, la sérine thréonine kinase RSK2, ayant un rôle dans le contrôle de l’apoptose des cellules de LAM. Mes collègues et moi-même avons montré que RSK2 était fortement diminuée suite à l’invalidation de PIM2 par interférence ARN dans une lignée de LAM FLT3-ITD (MOLM-14), tant au niveau ARNm que protéique. Par une technique de sensibilisation à l’apoptose à l’aide de peptides BH3 ainsi que par un inhibiteur de Bcl-2, le composé ABT-199, nous avons montré le rôle de RSK2 dans le contrôle de l’apoptose mitochondriale en contexte FLT3-ITD. Nous avons ensuite observé que la surexpression de RSK2 compensait la mort cellulaire induite par l’invalidation de PIM2, renforçant ainsi le rôle de cette nouvelle voie dans le contrôle de la survie cellulaire. Finalement, nous avons suggéré dans des modèles murins de la maladie que RSK2 pourrait participer à la résistance aux ITK ciblant FLT3. Afin de poser la question de ces mécanismes de résistance sans à priori, j’ai adapté à notre modèle de LAM une banque CRISPR pan-génomique dans le but de la cribler avec différents ITK et mettre à jour de nouveaux mécanismes de résistance aux ITK. J’ai utilisé l’enzyme dCas9 permettant non pas des cassures de l’ADN mais une modulation de la transcription de gènes cibles, soit une répression lors de la fusion au corépresseur KRAB (CRISPRi), soit une activation lors de la fusion à VP64 (CRISPRa). La dCas9 et les banques ont été transduites par des lentivirus dans 2 lignées FLT3-ITD (MOLM-14 et MV4-11). Ces cellules ont été amplifiées en culture liquide ou sur des cellules stromales mésenchymateuses (MSC) et traitées soit par du DMSO soit par l’un des 3 ITK ciblant FLT3 suivants : quizartinib, midostaurine ou ponatinib. L’identification et la quantification des ARN guides par séquençage haut débit et l’analyse bioinformatique nous renseigne enfin sur les gènes dont la répression favorise l’effet des ITK, pouvant ainsi représenter de nouveaux mécanismes de résistance intrinsèques (culture liquide) et/ou extrinsèques (co-culture MSCs) à la cellule. Le troisième axe de mon travail a porté sur la caractérisation des modifications du profil de signalisation global induites par les mutations du domaine tyrosine kinase (TKD) de FLT3-ITD impliquées dans la résistance aux ITK<br>Acute myeloid leukemia (AML) is a heterogeneous group of hematological malignancies resulting from the clonal proliferation of a myeloid progenitor blocked in its differentiation. The prognosis of AML is generally unfavorable, depending on age, cytogenetic and molecular factors. The FLT3-ITD mutation, (internal tandem duplication) is detected in 30% of AML patients and correlates with an increased frequency of relapses and an unfavorable prognosis. FLT3-ITD mutations leads to a deregulated and constitutive activation of FLT3 receptors, inducing an oncogenic addiction of leukemic blasts to FLT3-dependent signaling pathways, pinpointing FLT3 as a relevant therapeutic target in AML. Thus, many tyrosine kinase inhibitors (TKI) targeting FLT3 have been developed, some of which harboring significant efficacy in monotherapy and even improving patients’ survival when combined with conventional treatments. However, most patients treated by TKI monotherapy, and a significant proportion of those treated with combined approaches will relapse, due to various escape mechanisms. To study these mechanisms is therefore a major goal to improve the efficacy of treatments in FLT3-ITD LAM which I undertook during my thesis. First, I built on my team’s previous work to discover a new target of PIM2, the RSK2 serine threonine kinase, using transcriptomic and proteomic approaches. We showed that RSK2 expression was greatly decreased following the invalidation of PIM2 by RNA interference in a FLT3-ITD AML line (MOLM-14), both at the mRNA and protein levels. By BH3 profiling, we connected RSK2 to the control of mitochondrial apoptosis in the context of FLT3-ITD cells. We then observed that RSK2 overexpression compensated apoptosis induced by PIM2 knockdown, thus reinforcing the role of this new PIM2/RSK2 pathway in the control of cell survival. Finally, we suggested that RSK2 may be involved in TKI resistance in mouse models of AML. To address the question of FLT3-ITD resistance mechanisms more broadly, I adapted a CRISPR/dCas genome wide library on our AML model, with the purpose of screening it with different TKI to unravel new mechanisms of resistance to these compounds. I used the dCas9 enzyme, devoid of endonuclease activity but modulating target genes expression; inhibition in case of dCas9/KRAB fusion (CRISPRi), or activation in dCas9/VP64 fusion (CRISPRa). Both dCas9 and libraries were transduced by lentiviruses in two FLT3-ITD cell lines (MOLM-14 and MV4-11), grown in liquid culture or on a mesenchymal stromal cells (MSC) layer, and treated either with DMSO or with one of the 3 following ITKs: quizartinib, midostaurine or ponatinib. The identification and quantification of RNAs guides by high-throughput sequencing and bioinformatic identify potential new mechanisms of intrinsic resistance (liquid culture) and / or extrinsic (co-culture MSCs) to TKI. The third area of my work focused on the characterization of global signaling changes induced by FLT3-ITD tyrosine kinase domain (TKD) mutations associated with TKI resistance
Livres sur le sujet "Tyrosine Kinase Inhibitors (TKIs)"
1
Focosi, Daniele, ed. Resistance to Tyrosine Kinase Inhibitors. Springer International Publishing, 2016. http://dx.doi.org/10.1007/978-3-319-46091-8.
Texte intégral
2
D, Fabbro, and McCormick Frank 1950-, eds. Protein tyrosine kinases: From inhibitors to useful drugs. Humana Press, 2006.
Trouver le texte intégral
3
Rommel, Christian. Phosphoinositide 3-kinase in Health and Disease: Volume 2. Springer-Verlag Berlin Heidelberg, 2011.
Trouver le texte intégral
4
Matthews, David J. Targeting protein kinases for cancer therapy. John Wiley & Sons, 2009.
Trouver le texte intégral
5
Focosi, Daniele. Resistance to Tyrosine Kinase Inhibitors. Springer International Publishing AG, 2018.
Trouver le texte intégral
6
Focosi, Daniele. Resistance to Tyrosine Kinase Inhibitors. Springer, 2016.
Trouver le texte intégral
7
Focosi, Daniele. Resistance to Tyrosine Kinase Inhibitors. Springer, 2016.
Trouver le texte intégral
8
McCormick, Frank. Protein Tyrosine Kinases: From Inhibitors to Useful Drugs. Humana Press, 2005.
Trouver le texte intégral
9
McCormick, Frank, and Doriano Fabbro. Protein Tyrosine Kinases: From Inhibitors to Useful Drugs. Humana Press, 2010.
Trouver le texte intégral
10
(Editor), Doriano Fabbro, and Frank McCormick (Editor), eds. Protein Tyrosine Kinases: From Inhibitors to Useful Drugs (Cancer Drug Discovery and Development). Humana Press, 2005.
Trouver le texte intégralChapitres de livres sur le sujet "Tyrosine Kinase Inhibitors (TKIs)"
1
Kozan, Esin Oguz, and Eyup Naci Tiftik. "Immunotherapy in Chronic Leukemias." In Immunotherapy in Human Cancers. Nobel Tip Kitabevleri, 2024. http://dx.doi.org/10.69860/nobel.9786053359388.7.
Texte intégralRésumé :
Chronic myelogenous leukemia (CML) is a clonal myeloproliferative hematopoietic stem cell disorder. The most important immunotherapeutic drugs in the treatment of CML are tyrosine kinase inhibitors (TKI) and interferon. Chronic lymphocytic leukemia, another type of chronic leukemia, is one of the B cell chronic lymphoproliferative disorders. It is used in the treatment of three types of drug groups: anti-CD20 monoclonal antibodies, anti-CD19 monoclonal antibodies and bruton thyrosine kinase inhibitors.
2
Finessi, M., V. Liberini, and D. Deandreis. "Definition of Radioactive Iodine Refractory Thyroid Cancer and Redifferentiation Strategies." In Integrated Diagnostics and Theranostics of Thyroid Diseases. Springer International Publishing, 2023. http://dx.doi.org/10.1007/978-3-031-35213-3_9.
Texte intégralRésumé :
AbstractDifferentiated Thyroid Cancer (DTC) presents a 10-year survival rate of > 90% in case of localized disease while in case of distant metastases prognosis is poorer. Radioactive iodine is the first-line therapy for ablation, adjuvant intent, and for the treatment of distant metastases.In case of distant metastases, 50% of these patients obtain complete remission or stabilization of the disease over a long-term period with RAI therapy. Unfortunately, the remaining 50% of these patients, with the most aggressive and rapidly progressive disease, develop a RAI refractory disease thyroid cancer with loss of the ability to concentrate RAI or disease progression despite RAI uptake and with consequently poor outcomes (5-year disease-specific survival rates of 60–70% and a 10-year survival rate of 10%). In these patients, other treatment modalities including locoregional or systemic treatment by tyrosine kinase inhibitors (TKIs) should be preferred. Nevertheless, the definition of refractory thyroid cancer is still challenging and the decision to stop radioactive iodine and switch the therapeutic approach is still based on an individualized choice.Finally, a new approach by redifferentiation strategies combining TKI treatment and radioactive iodine is very promising for refractory and slowly progressive tumors.
3
Cakar, Burcu, and Erdem Göker. "Tyrosine Kinase Inhibitors." In Breast Disease. Springer International Publishing, 2016. http://dx.doi.org/10.1007/978-3-319-26012-9_36.
Texte intégral
4
Cakar, Burcu, and Erdem Göker. "Tyrosine Kinase Inhibitors." In Breast Disease. Springer International Publishing, 2019. http://dx.doi.org/10.1007/978-3-030-16792-9_35.
Texte intégral
5
Duhé, Roy J. "Tyrosine Kinase Inhibitors." In Encyclopedia of Cancer. Springer Berlin Heidelberg, 2015. http://dx.doi.org/10.1007/978-3-642-27841-9_6080-2.
Texte intégral
6
Abad, Cybele Lara R., and Raymund R. Razonable. "Tyrosine-Kinase Inhibitors." In Infectious Complications in Biologic and Targeted Therapies. Springer International Publishing, 2022. http://dx.doi.org/10.1007/978-3-031-11363-5_15.
Texte intégral
7
Duhé, Roy J. "Tyrosine Kinase Inhibitors." In Encyclopedia of Cancer. Springer Berlin Heidelberg, 2017. http://dx.doi.org/10.1007/978-3-662-46875-3_6080.
Texte intégral
8
Duhé, Roy J. "Tyrosine Kinase Inhibitors." In Encyclopedia of Cancer. Springer Berlin Heidelberg, 2011. http://dx.doi.org/10.1007/978-3-642-16483-5_6080.
Texte intégral
9
Champagne, Trevor. "Tyrosine-Kinase Inhibitors." In Litt's Drug Eruption & Reaction Manual, 31st ed. CRC Press, 2025. https://doi.org/10.1201/9781003569756-1524.
Texte intégral
10
Latham, Antony M., Jayakanth Kankanala, and Sreenivasan Ponnambalam. "Receptor Tyrosine Kinase Inhibitors." In Encyclopedia of Cancer. Springer Berlin Heidelberg, 2015. http://dx.doi.org/10.1007/978-3-642-27841-9_7196-1.
Texte intégralActes de conférences sur le sujet "Tyrosine Kinase Inhibitors (TKIs)"
1
Yalcin, Huseyin, Hissa Al-Thani, and Samar Shurbaji. "Development and In Vivo Testing of Smart Nanoparticles for Enhanced Anti-Cancer Activity and Reduced Cardiotoxicity Associated with Tyrosine Kinase Inhibitors." In Qatar University Annual Research Forum & Exhibition. Qatar University Press, 2021. http://dx.doi.org/10.29117/quarfe.2021.0088.
Texte intégralRésumé :
Tyrosine kinase inhibitors (TKIs) are new generation of anti-cancer drugs with very high efficiency against cancer cells. However, TKIs are associated with severe cardiotoxicity limiting their clinical benefits. One TKI that has been developed recently but not explored much is Ponatinib. The use of nanoparticles as a better therapeutic agent to deliver anti-cancer drugs and reduce their cardiotoxicity has been recently considered. In this study, PLGA-PEG-PLGA nanoparticles were synthesized to deliver Ponatinib while reducing its cardiotoxicity for treatment of chronic myeloid leukemia. Shape, size, surface charge and drug uptake ability of these nanoparticles were assessed using transmission electron microscopy (TEM), ZetaSIZER NANO and high-performance liquid chromatography (HPLC). Cardiotoxicity of Ponatinib, unloaded and loaded PLGA-PEG-PLGA nanoparticles were studied on zebrafish model through measuring the survival rate and cardiac function parameters, to optimize efficient drug concentrations in an in vivo setting. These particles were tested on zebrafish cancer xenograft model in which, K562 cell line, was transplanted into zebrafish embryos. We showed that, at an optimal concentration (0.0025mg/ml), Ponatinib loaded PLGA-PEG-PLGA particles are non-toxic/non-cardio-toxic and are very efficient against cancer growth and metastasis. Zebrafish is a good animal model for investigating the cardiotoxicity associated with the anti-cancer drugs such as TKIs, to determine the optimum concentration of smart nanoparticles with the least side effects and to generate xenograft model of several cancer types. Also, PLGA-PEG-PLGA NPs could be good candidate for CML treatment, but their cellular internalization should be enhanced. This could be achieved by coating and labeling the surface of PLGA-PEG-PLGA NPs with specific ligands that are unique to CML cells.
2
Kapoor, Gurpreet Singh, Yi Zhan, Heather Fetting, and Donald M. O'Rourke. "Abstract LB-11: PTEN modulates EGFRvIII-induced SHP2 phosphorylation and translocation to affect glioblastoma sensitivity to tyrosine kinase inhibitors (TKIs)." In Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1538-7445.am2011-lb-11.
Texte intégral
3
Honeywell, Richard J., Sarina Hitzerd, Ietje Kathmann, Elisa Giovannetti, Henk Verheul, and Frits Peters. "Abstract 4425: Characterisation of cellular transport and accumulation of six clinically approved tyrosine kinase inhibitors (TKIs) in colon cancer cells." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-4425.
Texte intégral
4
Cascone, Tina, Matthew H. Herynk, Li Xu, et al. "Abstract 376: Increased HGF is associated with resistance to VEGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC)." In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-376.
Texte intégral
5
Zhao, Jane, Adriana Guerrero, Kevin Kelnar, Heidi J. Peltier, and Andreas G. Bader. "Abstract 4814: miRNA combination therapy:In vitroanticancer synergy between miR-34a mimic and next generation EGFR tyrosine kinase inhibitors (TKIs) in NSCLC." In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-4814.
Texte intégral
6
Ward, Richard A., Ambra Bianco, Nicola Colclough, et al. "Abstract 4813: Comparative activity profiling of tyrosine kinase inhibitors (TKIs) against exon 20 insertions and the wild-type form of epidermal growth factor receptor (EGFR)." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-4813.
Texte intégral
7
Ward, Richard A., Ambra Bianco, Nicola Colclough, et al. "Abstract 4813: Comparative activity profiling of tyrosine kinase inhibitors (TKIs) against exon 20 insertions and the wild-type form of epidermal growth factor receptor (EGFR)." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.am2019-4813.
Texte intégral
8
Papayannidis, Cristina, Ilaria Iacobucci, Simona Soverini, et al. "Abstract 1804: Efficacy and clinical outcome of Philadelphia (Ph) positive acute lymphoblastic leukemia (ALL) patients treated with second generation tyrosine kinase inhibitors (TKIs): The Bologna experience." In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-1804.
Texte intégral
9
Lee, N., JL Lee, and JY Lee. "5PSQ-005 Analysis of anti-angiogenesis-related adverse events associated with vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) in patients with metastatic renal cell carcinoma." In 27th EAHP Congress, Lisbon, Portugal, 22-23-24 March 2023. British Medical Journal Publishing Group, 2023. http://dx.doi.org/10.1136/ejhpharm-2023-eahp.233.
Texte intégral
10
Fan, Ni, Yiyu Zou, Balazs Halmos, Roman Perez-Soler, and Haiying Cheng. "Abstract 4748: RICTOR signaling modulates the activity of EGFR tyrosine kinase inhibitors (TKI) inEGFR-mutated non-small cell lung cancer (NSCLC)." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-4748.
Texte intégralRapports d'organisations sur le sujet "Tyrosine Kinase Inhibitors (TKIs)"
1
Song, Yaowen, Shuiyu Lin, Jun Chen, Silu Ding, and Jun Dang. First-line treatment with TKI plus brain radiotherapy vs TKI alone in EGFR-mutated non-small-cell lung cancer with brain metastases: a systematic review and meta-analysis. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, 2023. http://dx.doi.org/10.37766/inplasy2023.1.0013.
Texte intégralRésumé :
Review question / Objective: It remains uncertain whether first-line treatment with upfront brain radiotherapy (RT) in combination with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is superior to EGFR-TKIs alone in EGFR-mutated non-small-cell lung cancer with newly diagnosed brain metastases (BMs). We performed a meta-analysis to address this issue. Condition being studied: Brain radiotherapy (RT) has been shown to damage the blood-brain barrier (BBB) and improve the concentration of EGFR-TKIs in the CSF. Additionally, RT can result in a reduction of EGFR-TKIs resistance. Therefore, EGFR-TKIs in combination with brain RT should be more effective than EGFR-TKIs alone theoretically. However, results from retrospective studies are inconsistent. There is the possibility that patients characteristics or brain RT technique affect the efficacy of treatments. To date, there is still no randomized controlled trials (RCTs) comparing the two treatment strategies.
2
Miller, Tod. Peptide-Bassed Inhibitors of Neu Tyrosine Kinase. Defense Technical Information Center, 1999. http://dx.doi.org/10.21236/ada375133.
Texte intégral
3
Miller, W. T. Peptide-Based Inhibitors of Neu Tyrosine Kinase. Defense Technical Information Center, 2000. http://dx.doi.org/10.21236/ada392289.
Texte intégral
4
Rosen, Neal. Development of Targeted Ansamycins as Novel Antiestrogens and Tyrosine Kinase Inhibitors. Defense Technical Information Center, 1998. http://dx.doi.org/10.21236/ada369205.
Texte intégral
5
Rosen, Neal. Development of Targeted Ansamycins as Noval Antiestrogens and Tyrosine Kinase Inhibitors. Defense Technical Information Center, 2000. http://dx.doi.org/10.21236/ada413599.
Texte intégral
6
Tinker, Anna V., Neesha C. Dhani, Prafull Ghatage, et al. Immune Checkpoint Inhibitors in Pretreated Metastatic Endometrial Cancer. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, 2023. http://dx.doi.org/10.37766/inplasy2023.1.0038.
Texte intégralRésumé :
Review question / Objective: Efficacy and safety of immune checkpoint inhibitors alone or in combination with tyrosine kinase inhibitors in patients with pretreated advanced, persistent, or recurrent metastatic endometrial cancer. Condition being studied: Advanced, persistent, or recurrent metastatic endometrial cancer. Study designs to be included: Non-randomized studies of monotherapy in populations selected for relevant biomarkers such as MMR, microsatellite stability, and PD-L1 expression status and randomized trials of ICI combinations in unselected patients.
7
Chen, Yueying, Yanjun Du, Dong Wang, Ping Zhan, Hedong Han, and Tangfeng Lv. New Options for Advanced NSCLC Patients Resistant to EGFR Tyrosine Kinase Inhibitors – A Systematic Review and Network Meta-analysis. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, 2025. https://doi.org/10.37766/inplasy2025.1.0014.
Texte intégral
8
Wang, Zexian, Yaru Guo, Xiaojin Wu, Xiaohan Qin, Zhiling Wan, and Chen Liu. Bevacizumab plus Epidermal Growth Factor Receptor (EGFR)-Tyrosine Kinase Inhibitor versus EGFR-TKI alone for advanced EGFR-mutant non-small cell lung cancer: a meta-analysis of randomized clinical trials. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, 2023. http://dx.doi.org/10.37766/inplasy2023.12.0059.
Texte intégral
9
Qin, Xiaohan, Yaru Guo, Xiaojin Wu, Zexian Wang, Zhiling Wan, and Chen Liu. Chemotherapy plus Epidermal Growth Factor Receptor (EGFR)-Tyrosine Kinase Inhibitor versus EGFR-TKI alone for advanced EGFR-mutant non-small cell lung cancer: a meta-analysis of randomized clinical trials. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, 2024. http://dx.doi.org/10.37766/inplasy2024.1.0128.
Texte intégral
10
Liu, Xionglin, Jindu Li, Minjun Li, and Bangde Xiang. Efficacy and Safety of Tyrosine Kinase Inhibitors in Advanced Hepatocellular Carcinoma Patients with Child-Pugh A and B Cirrhosis: A Meta-Analysis. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, 2024. http://dx.doi.org/10.37766/inplasy2024.10.0130.
Texte intégral