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Journal articles on the topic 'EGFR-Inhibition'

Author: Grafiati
Published: 4 June 2021
Last updated: 6 July 2024

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1

Gursel, Demirkan B., Cody D. Schlaff, and John A. Boockvar. "EGFR Targeted Inhibition Resistance." Neurosurgery 71, no. 4 (October 2012): N17—N18. http://dx.doi.org/10.1227/01.neu.0000419710.25405.7f.

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2

Gaipl, Udo S. "EGFR-Inhibition bei NSCLC-Tumorzelllinien." Strahlentherapie und Onkologie 192, no. 6 (May 11, 2016): 425–27. http://dx.doi.org/10.1007/s00066-016-0977-9.

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3

Patel, Rajvi. "EGFR Signaling and its inhibition by EGFR inhibitors in NSCLC." International Journal of Applied Sciences and Biotechnology 2, no. 4 (December 25, 2014): 375–88. http://dx.doi.org/10.3126/ijasbt.v2i4.11263.

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Lung cancer is the third most cancer among the population. The American society’s estimation for lung cancer in the United States for 2014 states that about 2,24,210 people are suffering from the lung cancer and 1,59,260 deaths are occur from lung cancer. Among all the types of lung cancer, NSCLC (Non-Small cell Lung Cancer) represents 85% of the lung cancer. The estimated spread of NSCLC is 2,26,160 and 1,60,340 cases are of death in 2012. One of the risk factor for NSCLC is over expression of epidermal growth factor receptor (EGFR) and its intracellular signaling pathways. EGFR is over expressed in 40-80 % cases of NSCLC. EGFR belongs to the ErbB family of receptor tyrosinekinases (RTK) having molecular weight 170 to 185 kDa. Epidermal Growth Factor (EGF) binds to the EGFR at its extracellular domain and this binding leads to the homo or hetero dimerization and autophosphorylation of EGFR which initiates the several intracellular pathways. Several mutations in EGFR or in any of the proteins of the pathway leads to the growth and survival of the tumor cells. So in order to inhibit the growth of tumor cell, several EGFR inhibitors and targeted therapies are found to target the particular mutations.DOI: http://dx.doi.org/10.3126/ijasbt.v2i4.11263 Int J Appl Sci Biotechnol, Vol. 2(4): 375-388
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4

Kalyankrishna, Shailaja, and Jennifer R. Grandis. "Epidermal Growth Factor Receptor Biology in Head and Neck Cancer." Journal of Clinical Oncology 24, no. 17 (June 10, 2006): 2666–72. http://dx.doi.org/10.1200/jco.2005.04.8306.

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Epidermal growth factor receptor (EGFR) is overexpressed in several epithelial malignancies, including head and neck squamous cell carcinoma (HNSCC), which exhibits EGFR overexpression in up to 90% of tumors. EGFR ligands such as transforming growth factor alpha are also overexpressed in HNSCC. EGFR plays a critical role in HNSCC growth, invasion, metastasis and angiogenesis. However, EGFR inhibitors as monotherapy have yielded only modest clinical outcomes. Potential mechanisms for lack of response to EGFR inhibition in HNSCC include constitutive activation of signaling pathways independent of EGFR, as well as genetic aberrations causing dysregulation of the cell cycle. EGFR-directed therapy may be optimized by identifying and selecting those HNSCC patients most likely to benefit from EGFR inhibition. Resistance to EGFR inhibition may be circumvented by combination therapy employing EGFR inhibitors together with other treatment modalities.
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5

Guo, Gao, Ke Gong, Jann Sarkaria, and Amyn Habib. "DRES-01. EFFICACY OF EGFR PLUS TNF INHIBITION IN A PRECLINICAL MODEL OF GLIOBLASTOMA." Neuro-Oncology 21, Supplement_6 (November 2019): vi71. http://dx.doi.org/10.1093/neuonc/noz175.289.

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Abstract EGFR gene amplification and mutation are common in glioblastoma (GBM), but EGFR inhibition is not effective in treating this tumor. EGFR inhibition may fail because EGFR is not a driver of the malignant phenotype in GBM, or because adaptive compensatory mechanisms are triggered by EGFR inhibition that prevent cell death from a loss of EGFR signaling. We have recently identified a TNFα-JNK-Axl-ERK signaling axis that mediates primary resistance to EGFR inhibition in GBM. Temozolomide (TMZ) is the most effective chemotherapy in GBM, although it has only a modest effect on overall survival. The efficacy of TMZ depends on the absence of the DNA repair protein O6-alkylguanine DNA alkyltransferase (MGMT) which reverses the DNA damage induced by TMZ. The MGMT promoter is hypermethylated in about 45% of GBMs, resulting in lack of MGMT expression. TMZ is less effective in MGMT unmethylated GBMs. Moreover, even initially responsive tumors develop a secondary resistance to TMZ. No treatment is effective in recurrent TMZ-resistant GBM. In this study, we compare the efficacy of temozolomide versus EGFR plus TNF inhibition in an orthotopic model of GBM. We find that efficacy of the two treatments is similar in MGMT-methylated GBMs. However, in MGMT-unmethylated GBMs, a combination of EGFR plus TNF inhibition is more effective. We demonstrate that the two treatment approaches target distinct and non-overlapping pathways. Furthermore, and importantly, EGFR plus TNF inhibition remains effective in TMZ-resistant recurrent GBMs and in GBMs rendered experimentally resistant to TMZ. Since the EGFR is expressed in the majority of GBMs, EGFR inhibition combined with a blunting of the accompanying TNF-driven adaptive response could be a broadly applicable and viable therapeutic approach in primary GBMs with MGMT unmethylation and in recurrent GBMs.
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6

Corkery, B., N. O’Donovan, M. Clynes, and J. Crown. "Epidermal growth factor receptor (EGFR) inhibition in triple-negative breast cancer (BrCa)." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 14071. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.14071.

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14071 Background: Triple-negative BrCa lacks expression of hormone receptors and HER-2 but does express EGFR. It is associated with early relapse and poor survival. There is no targeted therapy for triple-negative BrCa. We are studying the potential role of EGFR inhibition. Methods: EGFR expression was examined in triple-negative BrCa cell lines, (BT20, HCC1937, and MDA-MB-231) by western blot. IC50 assays were determined for three EGFR inhibitors, gefitinib (G) and erlotinib (T), which are small-molecule tyrosine kinase inhibitors, and cetuximab (E) which is a monoclonal antibody against EGFR, and chemotherapy (CRx) drugs docetaxel (D) and carboplatin (P)), using the acid phosphatase assay. The controls were HER2+ BrCa cell lines, BT474 and SKBR3 which express low levels of EGFR. Results: The three triple-negative cell lines over-express EGFR. IC50 values for G and T were significantly higher in the triple-negative than in the HER2+ cell lines. E did not cause significant inhibition in any cell line (max inhibition 20% at 100 μg/ml E). IC50 values for G were lower than for T in the triple-negative cell lines (IC50s for HCC1937: G - 8.4 ± 1.5 μM; T - 26.2 ± 9.3 μM). Combined EGFR inhibition with CRx was tested in HCC1937 cells. G combined with P or with D for 5 days showed an additive effect on inhibition of proliferation ( Table 1 ). Alternate scheduling of the drugs did not significantly influence response. Conclusions: Our results suggest that triple-negative BrCa cells over-express EGFR but are not as sensitive to EGFR inhibition as HER2+ BrCa cells. However, EGFR inhibition may enhance response to CRx in triple-negative BrCa. [Table: see text] No significant financial relationships to disclose.
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7

Guo, Gao, Ke Gong, Vineshkumar Thidil Puliyappadamba, Nishah Panchani, Edward Pan, Bipasha Mukherjee, Ziba Damanwalla, et al. "Efficacy of EGFR plus TNF inhibition in a preclinical model of temozolomide-resistant glioblastoma." Neuro-Oncology 21, no. 12 (July 31, 2019): 1529–39. http://dx.doi.org/10.1093/neuonc/noz127.

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Abstract Background Glioblastoma (GBM) is the most common primary malignant adult brain tumor. Temozolomide (TMZ) is the standard of care and is most effective in GBMs that lack the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). Moreover, even initially responsive tumors develop a secondary resistance to TMZ and become untreatable. Since aberrant epidermal growth factor receptor (EGFR) signaling is widespread in GBM, EGFR inhibition has been tried in multiple clinical trials without success. We recently reported that inhibiting EGFR leads to increased secretion of tumor necrosis factor (TNF) and activation of a survival pathway in GBM. Here, we compare the efficacy of TMZ versus EGFR plus TNF inhibition in an orthotopic mouse model of GBM. Methods We use an orthotopic model to examine the efficacy of TMZ versus EGFR plus TNF inhibition in multiple subsets of GBMs, including MGMT methylated and unmethylated primary GBMs, recurrent GBMs, and GBMs rendered experimentally resistant to TMZ. Results The efficacy of the 2 treatments was similar in MGMT methylated GBMs. However, in MGMT unmethylated GBMs, a combination of EGFR plus TNF inhibition was more effective. We demonstrate that the 2 treatment approaches target distinct and non-overlapping pathways. Thus, importantly, EGFR plus TNF inhibition remains effective in TMZ-resistant recurrent GBMs and in GBMs rendered experimentally resistant to TMZ. Conclusion EGFR inhibition combined with a blunting of the accompanying TNF-driven adaptive response could be a viable therapeutic approach in MGMT unmethylated and recurrent EGFR-expressing GBMs.
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8

Harris, Zachary M., Ying Sun, John Joerns, Brian Clark, Buqu Hu, Asawari Korde, Lokesh Sharma, et al. "Epidermal Growth Factor Receptor Inhibition Is Protective in Hyperoxia-Induced Lung Injury." Oxidative Medicine and Cellular Longevity 2022 (September 20, 2022): 1–18. http://dx.doi.org/10.1155/2022/9518592.

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Aims. Studies have linked severe hyperoxia, or prolonged exposure to very high oxygen levels, with worse clinical outcomes. This study investigated the role of epidermal growth factor receptor (EGFR) in hyperoxia-induced lung injury at very high oxygen levels (>95%). Results. Effects of severe hyperoxia (100% oxygen) were studied in mice with genetically inhibited EGFR and wild-type littermates. Despite the established role of EGFR in lung repair, EGFR inhibition led to improved survival and reduced acute lung injury, which prompted an investigation into this protective mechanism. Endothelial EGFR genetic knockout did not confer protection. EGFR inhibition led to decreased levels of cleaved caspase-3 and poly (ADP-ribosyl) polymerase (PARP) and decreased terminal dUTP nick end labeling- (TUNEL-) positive staining in alveolar epithelial cells and reduced ERK activation, which suggested reduced apoptosis in vivo. EGFR inhibition decreased hyperoxia (95%)-induced apoptosis and ERK in murine alveolar epithelial cells in vitro, and CRISPR-mediated EGFR deletion reduced hyperoxia-induced apoptosis and ERK in human alveolar epithelial cells in vitro. Innovation. This work defines a protective role of EGFR inhibition to decrease apoptosis in lung injury induced by 100% oxygen. This further characterizes the complex role of EGFR in acute lung injury and outlines a novel hyperoxia-induced cell death pathway that warrants further study. Conclusion. In conditions of severe hyperoxia (>95% for >24 h), EGFR inhibition led to improved survival, decreased lung injury, and reduced cell death. These findings further elucidate the complex role of EGFR in acute lung injury.
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9

Warta, Rolf, and Christel Herold-Mende. "Helping EGFR inhibition to block cancer." Nature Neuroscience 20, no. 8 (July 26, 2017): 1035–37. http://dx.doi.org/10.1038/nn.4605.

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10

Martz, Lauren. "EGFR inhibition boosts stem cell mobilization." Science-Business eXchange 3, no. 40 (October 2010): 1197. http://dx.doi.org/10.1038/scibx.2010.1197.

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11

Killock, David. "A new generation of EGFR inhibition." Nature Reviews Clinical Oncology 12, no. 7 (May 12, 2015): 373. http://dx.doi.org/10.1038/nrclinonc.2015.93.

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12

Pander, Jan, Hans Gelderblom, and Henk-Jan Guchelaar. "Pharmacogenetics of EGFR and VEGF inhibition." Drug Discovery Today 12, no. 23-24 (December 2007): 1054–60. http://dx.doi.org/10.1016/j.drudis.2007.10.016.

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13

Engel, Julian, Christian Becker, Jonas Lategahn, Marina Keul, Julia Ketzer, Thomas Mühlenberg, Laxmikanth Kollipara, et al. "Inhibition wirkstoffresistenter Mutationsvarianten der Rezeptortyrosinkinase EGFR." Angewandte Chemie 128, no. 36 (August 5, 2016): 11069–73. http://dx.doi.org/10.1002/ange.201605011.

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14

Liu, W., A. A. Akhand, M. Kato, I. Yokoyama, T. Miyata, K. Kurokawa, K. Uchida, and I. Nakashima. "4-hydroxynonenal triggers an epidermal growth factor receptor-linked signal pathway for growth inhibition." Journal of Cell Science 112, no. 14 (July 15, 1999): 2409–17. http://dx.doi.org/10.1242/jcs.112.14.2409.

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Lipid peroxidation has been implicated in the pathogenesis of various diseases. As a major product of membrane lipid peroxidation, 4-hydroxynonenal (HNE) appears after various kinds of oxidative stress, and is known to induce cell growth inhibition. We here analysed the HNE-mediated signal transduction cascade for the growth inhibition of human epidermoid carcinoma A431 cells. HNE dose-dependently induced phosphorylation of multiple cellular proteins including epidermal growth factor receptor (EGFR) in A431 cells, and rapidly upregulated the catalytic actions of EGFR for autophosphorylation and for phosphorylation of casein as an exogenous substrate. Immunoblot analysis by use of HNE-specific antibody demonstrated the binding of HNE to EGFR along with its activation. This binding, which did not induce cross-linking of EGFR, caused a capping of the receptor on the cell surface which mimicked the capping induced by EGF. Phosphorylation and activation of EGFR were followed by phosphorylation of adaptor protein Shc and activation of MAP kinase. Both genistein as a wide spectrum protein tyrosine kinase inhibitor and AG1478 as a specific EGFR tyrosine phosphorylation blocker inhibited activation of EGFR and MAP kinase by HNE. The same inhibitors prevented HNE-mediated growth inhibition, suggesting a close linkage between EGFR/MAP kinase activation and growth inhibition after exposure to HNE. Our results suggest that EGFR may be one of the primary targets of HNE for an oxidative stress-linked cell growth inhibition.
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15

Pozo, Natividad, Cristina Zahonero, Paloma Fernández, Jose M. Liñares, Angel Ayuso, Masatoshi Hagiwara, Angel Pérez, et al. "Inhibition of DYRK1A destabilizes EGFR and reduces EGFR-dependent glioblastoma growth." Journal of Clinical Investigation 123, no. 6 (May 1, 2013): 2475–87. http://dx.doi.org/10.1172/jci63623.

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16

Balko, Justin M., Brett R. Jones, Virginia L. Coakley, and Esther P. Black. "MEK and EGFR inhibition demonstrate synergistic activity in EGFR-dependent NSCLC." Cancer Biology & Therapy 8, no. 6 (March 15, 2009): 522–30. http://dx.doi.org/10.4161/cbt.8.6.7690.

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17

Noch, Evan, Iyad Alnahhas, Laura Palma, and Lewis Cantley. "EXTH-12. INHIBITION OF EPIDERMAL GROWTH FACTOR RECEPTOR AND PLATELET-DERIVED GROWTH FACTOR RECEPTOR-ALPHA EXERTS SYNERGISTIC EFFICACY IN GLIOBLASTOMA." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi165—vi166. http://dx.doi.org/10.1093/neuonc/noab196.651.

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Abstract Epidermal growth factor receptor (EGFR) alterations, including amplification and activating mutations, occur in more than half of GBM cases. EGFR is located on Chr. 7, and Chr. 7 gain is one of the earliest events precipitating gliomagenesis. EGFR inhibitors, monoclonal antibodies, vaccines, and CAR-T cells have failed in GBM due to intrinsic heterogeneity and receptor tyrosine kinase (RTK) bypass pathways that mediate therapeutic resistance. New targeted therapeutic approaches to leverage synergistic combinations are desperately needed to improve GBM prognosis. Using the TCGA and other GBM databases, we previously demonstrated that PDGFRA amplification in patients with EGFR-amplified GBM carries significantly worse survival. EGFR and PDGFRA co-expression occur in more than one-third of GBM patients. The PDGFRA ligand PDGFA is also located on Chr. 7, and its expression is significantly increased with Chr. 7 gain and EGFR copy number increase. Therefore, Chr. 7 gain inherently leads to co-activation of both EGFR and PDGFRA signaling. We used patient-derived glioblastoma cells with Chr. 7 gain to test combined inhibition of EGFR and PDGFRA in vitro. We found that combined inhibition of both EGFR and PDGFRA using FDA-approved EGFR-targeted agents (Erlotinib, Gefitinib, Dacomitinib, Neratinib, and Osimertinib) and Crenolanib, respectively, leads to synergistic cytotoxicity in vitro. Inhibition of either EGFR or PDGFRA led to receptor cross-activation, and EGF and PDGF-AA-induced RTK activation was blocked by Neratinib and Crenolanib. Immunoprecipitation experiments and proximity ligation assays demonstrated that combined inhibition prevents EGFR and PDGFRA heterodimerization and pathways of therapeutic resistance. This combined inhibition led to decreased activation of downstream signaling pathways, including PI3K and MAPK. We show that combined inhibition of EGFR and PDGFRA exerts synergistic cytotoxicity in GBM and prevents resistance pathways that emerge during single-agent targeted therapy. These pathways are targetable with FDA-approved agents that could be used in patients with GBM with Chr. 7 gain.
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Selenz, Carolin, Anik Compes, Marieke Nill, Sven Borchmann, Margarete Odenthal, Alexandra Florin, Johannes Brägelmann, Reinhard Büttner, Lydia Meder, and Roland T. Ullrich. "EGFR Inhibition Strongly Modulates the Tumour Immune Microenvironment in EGFR-Driven Non-Small-Cell Lung Cancer." Cancers 14, no. 16 (August 16, 2022): 3943. http://dx.doi.org/10.3390/cancers14163943.

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EGFR-driven non-small-cell lung cancer (NSCLC) patients are currently treated with TKIs targeting EGFR, such as erlotinib or osimertinib. Despite a promising initial response to TKI treatment, most patients gain resistance to oncogene-targeted therapy, and tumours progress. With the development of inhibitors against immune checkpoints, such as PD-1, that mediate an immunosuppressive microenvironment, immunotherapy approaches attempt to restore a proinflammatory immune response in tumours. However, this strategy has shown only limited benefits in EGFR-driven NSCLC. Approaches combining EGFR inhibition with immunotherapy to stimulate the immune response and overcome resistance to therapy have been limited due to insufficient understanding about the effect of EGFR-targeting treatment on the immune cells in the TME. Here, we investigate the impact of EGFR inhibition by erlotinib on the TME and its effect on the antitumour response of the immune cell infiltrate. For this purpose, we used a transgenic conditional mouse model to study the immunological profile in EGFR-driven NSCLC tumours. We found that EGFR inhibition mediated a higher infiltration of immune cells and increased local proliferation of T-cells in the tumours. Moreover, inhibiting EGFR signalling led to increased activation of immune cells in the TME. Most strikingly, combined simultaneous blockade of EGFR and anti-PD-1 (aPD-1) enhanced tumour treatment response in a transgenic mouse model of EGFR-driven NSCLC. Thus, our findings show that EGFR inhibition promotes an active and proinflammatory immune cell infiltrate in the TME while improving response to immune checkpoint inhibitors in EGFR-driven NSCLC.
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El-Abaseri, Taghrid Bahig, Brianna Hammiller, Susan K. Repertinger, and Laura A. Hansen. "The Epidermal Growth Factor Receptor Increases Cytokine Production and Cutaneous Inflammation in Response to Ultraviolet Irradiation." ISRN Dermatology 2013 (June 25, 2013): 1–11. http://dx.doi.org/10.1155/2013/848705.

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The epidermal growth factor receptor (EGFR) is activated in cutaneous keratinocytes upon ultraviolet (UV) exposure and has been implicated in ultraviolet-(UV-)induced inflammation and skin tumorigenesis. Egfr mutant mice and EGFR inhibitors were used to investigate the hypothesis that EGFR activation augments inflammation following UV irradiation. Topical treatment of mouse skin with the EGFR inhibitor AG1478 before UV exposure suppressed UV-induced erythema, edema, mast cell infiltration, and neutrophil infiltration. Genetic ablation of Egfr and EGFR inhibition by AG1478 also suppressed the increase in the proinflammatory cytokines tumor necrosis factor α (TNF-α), interleukin-1α, KC (murine IL-8), and cyclooxygenase-2 (COX-2) after UV exposure of cultured keratinocytes. Finally, genetic ablation of inhibition of EGFR in cultured keratinocytes decreased p38 activation after UV, while inhibition of p38 kinase reduced COX-2 expression after UV. These data demonstrate that EGFR regulates multiple aspects of UV-induced inflammation and suggest activation of p38 kinase leading to increased COX-2 and cytokine expression as one mechanism through which it acts.
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20

Heo, Jung Sun, Yun Jung Lee, and Ho Jae Han. "EGF stimulates proliferation of mouse embryonic stem cells: involvement of Ca2+ influx and p44/42 MAPKs." American Journal of Physiology-Cell Physiology 290, no. 1 (January 2006): C123—C133. http://dx.doi.org/10.1152/ajpcell.00142.2005.

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We examined the effect of EGF on the proliferation of mouse embryonic stem (ES) cells and their related signal pathways. EGF increased [3H]thymidine and 5-bromo-2′-deoxyuridine incorporation in a time- and dose-dependent manner. EGF stimulated the phosphorylation of EGF receptor (EGFR). Inhibition of EGFR tyrosine kinase with AG-1478 or herbimycin A, inhibition of PLC with neomycin or U-73122, inhibition of PKC with bisindolylmaleimide I or staurosporine, and inhibition of L-type Ca2+ channels with nifedipine or methoxyverapamil prevented EGF-induced [3H]thymidine incorporation. PKC-α, -βI, -γ, -δ, and -ζ were translocated to the membrane and intracellular Ca2+ concentration ([Ca2+]i) was increased in response to EGF. Moreover, inhibition of EGFR tyrosine kinase, PLC, and PKC completely prevented EGF-induced increases in [Ca2+]i. EGF also increased inositol phosphate levels, which were blocked by EGFR tyrosine kinase inhibitors. Furthermore, EGF rapidly increased formation of H2O2, and pretreatment with antioxidant ( N-acetyl-l-cysteine) inhibited EGF-induced increase of [Ca2+]i. In addition, we observed that p44/42 MAPK phosphorylation by EGF and inhibition of EGFR tyrosine kinase, PLC, PKC, or Ca2+ channels blocked EGF-induced phosphorylation of p44/42 MAPKs. Inhibition of p44/42 MAPKs with PD-98059 (MEK inhibitor) attenuated EGF-induced increase of [3H]thymidine incorporation. Finally, inhibition of EGFR tyrosine kinase, PKC, Ca2+ channels, or p44/42 MAPKs attenuated EGF-stimulated cyclin D1, cyclin E, cyclin-dependent kinase (CDK)2, and CDK4, respectively. In conclusion, EGF partially stimulates proliferation of mouse ES cells via PLC/PKC, Ca2+ influx, and p44/42 MAPK signal pathways through EGFR tyrosine kinase phosphorylation.
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21

Perez-Soler, R., Y. Zou, T. Li, C. Tornos, and Y. Ling. "Topical vitamin K3 (Vit K3, Menadione) prevents erlotinib and cetuximab-induced EGFR inhibition in the skin." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 3036. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.3036.

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3036 Background: The EGFR inhibitors erlotinib and cetuximab cause skin toxicity in about 75% of patients. The occurrence of skin toxicity correlates with clinical benefit. About half the patients with skin toxicity report significant discomfort. There are currently no scientifically based or proven methods for preventing or treating effectively the skin toxicity secondary to EGFR inhibitors. Methods: We screened a number of EGFR activators and phosphatase inhibitors for their ability to abrogate EGFR inhibition secondary to erlotinib and cetuximab in A431 cells. P-EGFR expression was assessed by western blot analysis. Vit K3 was selected for further in vivo studies. The skin toxicity secondary to the topical application of Vit K3 was evaluated in nude mice. The highest non-toxic concentration was used to determine the ability of topical Vit K3 to prevent EGFR inhibition in the skin of nude mice treated with EGFR inhibitors. Results: Vit K3 was the most potent EGFR activator identified, the maximum effect being observed at concentrations of 0.1–0.5 mM. In the presence of erlotinib or cetuximab, 0.1- 0.5 mM Vit K3 completely prevented EGFR inhibition. The maximum non-toxic concentration of Vit K3 applied topically BID × 10 days to nude mice was 15 mM. At this concentration, topical Vit K3 caused P-EGFR upregulation in the skin. In animals treated with erlotinib (100 mg/kg daily × 5 days), there was no detectable P-EGFR expression in the skin not treated with topical Vit K3 whereas P-EGFR expression was completely restored in the skin treated BID x 5 days with topical Vit K3. Conclusions: Vit K3 is one of the first reported agents to prevent/reverse EGFR inhibition secondary to anti-EGFR agents. The results strongly justify the development of a topical formulation of Vit K3 to treat and prevent the cutaneous toxicity secondary to EGFR inhibitors. [Table: see text]
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Bissonnette, R. P., B. Fan, K. Roegner, S. Ng, M. Corpuz, R. Prudente, A. Negro-Vilar, and W. Yen. "Cooperative antitumor activity between the retinoid X receptor (RXR)-selective agonist bexarotene and EGFR-tyrosine kinase inhibitors in preclinical models of NSCLC." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 17073. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.17073.

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17073 Background: Gefitinib and erlotinib, small molecule inhibitors of the EGFR-tyrosine kinase (EGFR-TKI), can have antitumor activity in patients with advanced NSCLC. However, analysis of clinical samples and in vitro characterization of NSCLC cell lines has revealed EGFR mutations that correlate with the clinical responses. While EGFR-mutant cell lines are hypersensitive to EGFR-TKI-mediated growth inhibition and have a greater tendency to undergo apoptosis in response to EGFR inhibition, wild-type EGFR cell lines undergo growth inhibition only at high concentrations, and are resistant to apoptosis induction. Bexarotene (Targretin) is a RXR modulator with clinical activity enhancing survival in a subset of NSCLC patients. We have shown that bexarotene can suppress the growth of epithelial tumors by modulating the expression and function of the EGFR pathway. This study examined the effect of bexarotene/EGFR-TKI combinations in preclinical models of NSCLC, and evaluated the possible molecular mechanisms for cooperative antitumor activity between these agents. Results: Bexarotene enhanced the activity of gefitinib in most of the cell lines tested, and did so regardless of their EGFR mutation status or intrinsic sensitivity to gefitinib alone. Resistant lines were sensitized by the combination, which decreased gefitinib IC50s to clinically achievable concentrations. Bexarotene increased the pro-apoptotic activity of both gefitinib and erlotinib, an effect which was paralleled by enhanced repression of p-Akt and p-Her2 levels by the combinations. In ex vivo cultures of human NSCLC explant tissue, the addition of bexarotene enhanced the growth inhibitory activity of both gefitinib and erlotinib. Finally, combinations of bexarotene and EGFR-TKI produced growth inhibition of TKI-resistant A427 NSCLC xenograft tumors that was superior to either agent alone. Conclusions: These results indicate that bexarotene can sensitize NSCLC cells which are unresponsive to the effects of EGFR-TKIs, resulting in cooperative growth inhibition and apoptosis induction. Combination therapy using bexarotene in conjunction with EGFR-TKIs may provide a powerful new therapeutic strategy. [Table: see text]
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23

Dowlati, Afshin, David Nethery, and Jeffrey A. Kern. "Combined inhibition of epidermal growth factor receptor and JAK/STAT pathways results in greater growth inhibition in vitro than single agent therapy." Molecular Cancer Therapeutics 3, no. 4 (April 1, 2004): 459–63. http://dx.doi.org/10.1158/1535-7163.459.3.4.

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Abstract Epidermal growth factor receptor (EGFR) inhibition with small molecule tyrosine kinase inhibitors results in antitumor activity in only a minority of patients whose tumors express EGFR. One hypothesis to explain this suboptimal clinical activity is that multiple growth regulatory pathways are abnormal in most EGFR-expressing cancers. Given the importance of Stat-3 signaling pathway in epidermoid tumors, we hypothesized that blocking complementary pathways in an epidermal growth factor (EGF)-driven model of proliferation in the A431 cell line would demonstrate improved antiproliferative activity. Exposure of A431 cells to the EGF results in a significant increase in EGFR and Stat-3 phosphorylation. However, inhibition of EGFR by AG1478 fails to decrease EGF-induced Stat-3 phosphorylation. This suggests that EGF continues to drive Stat-3 phosphorylation through other receptors. Our study suggests that residual ErbB2 activation by EGF, despite EGFR blockade, is responsible for persistent downstream activation of Stat-3. In this setting, combined exposure to an EGFR blocker and Stat-3 blocker (AG490) results in significantly greater tumor growth inhibition than either agent alone. We conclude that targeting multiple pathways (EGFR and JAK/STAT pathways) in EGF-driven tumors may result in greater antiproliferative activity than blocking EGFR alone.
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24

Kozlova, N. I., G. E. Morozevich, N. A. Ushakova, N. M. Gevorkian, and A. E. Berman. "Implication of integrin alpha5beta1 signal pathways in proliferation and apoptosis of MCF-7/Dox human breast carcinoma cells." Biomeditsinskaya Khimiya 62, no. 3 (2016): 272–78. http://dx.doi.org/10.18097/pbmc20166203272.

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In MCF-7/Dox human breast carcinoma cells, down-regulation of integrin alpha5beta1 and inhibition of epidermal growth factor receptor (EGFR) markedly reduced rates of cell proliferation. Mitotic cycle analysis showed that alpha5beta1 down-regulation resulted in cell cycle arrest at the S phase, followed by a significant increase in the population of apoptotic cells (subG1 population). Inhibition of EGFR activity also caused cell cycle arrest at the S-phase but without any increase in the subG1 population. Down-regulation of alpha5beta1 and EGFR inhibition resulted in a significant decrease of cell content of the active (phosphorylated) forms of FAK and Erk protein kinases. The data obtained suggest that alpha5beta1 integrin is implicated in cell growth control via inhibition of apoptotic cell death and through EGFR activation.
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Tsien, C., M. Nyati, D. Chepeha, F. Worden, J. Helman, C. Bradford, G. Wolf, T. Lawrence, and A. Eisbruch. "Differential tumor and normal mucosa biomarker modulation by epidermal growth factor receptor (EGFR) inhibition using erlotinib in oral cavity squamous cell carcinoma (OCSCC)." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 6077. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.6077.

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6077 Background: Targeted therapy may improve the therapeutic index in locally advanced head neck cancer if differential EGFR inhibition in tumors compared to the normal mucosa is demonstrated. Based on prior published data, EGFR degradation is an important biomarker of cytotoxicity in a preclinical model. The aim of this pilot study was to determine if there are differences in biomarker modulation between tumor and the normal mucosa and confirm our initial preclinical findings regarding EGFR degradation. Methods: Patients with primary OCSCC requiring surgical resection had normal mucosa and tumor biopsies prior to a test course of erlotinib. Patients received one week of erlotinib 150 mg qd. Repeat tumor and normal mucosal biopsies were obtained at the time of surgical resection to evaluate the effect of the EGFR inhibitor on both tumor and the normal mucosa. Changes in known preclinical markers of EGFR activity (phospho, total EGFR, AKT, STAT3) were measured by immunoblotting assays. In addition, changes in distribution of these biomarkers were analyzed by immunohistochemical analysis. Results: 12 pts were enrolled; 7 pts with paired tumor and normal mucosa biopsies. Tumor specimens showed over-expression of EGFR compared to the normal mucosa (p = 0.005). Erlotinib treatment led to marked inhibition of both pEGFR and EGFR protein (p = 0.004 and p = 0.007, respectively) in tumor biopsies. In contrast, we found heterogeneity in EGFR inhibition in the normal mucosa following erlotinib. (p = 0.1 [pEGFR], and p = 0.07 [EGFR)]) We noted dramatic reduced levels of pSrc and pSTAT3 following erlotinib in tumors compared to untreated matched tumor samples. In addition, levels of p27 were enhanced. Conclusions: Differential EGFR inhibition in tumors compared to the normal mucosa, may suggest that the addition of EGFR inhibitors to chemo-RT or accelerated RT, whose dose limiting toxicity is acute mucositis, may select patients who will benefit from targeted therapy. Our results demonstrate that EGFR inhibition by erlotinib led to marked reduction in EGFR protein levels. EGFR degradation may be an important biomarker in selecting patients predicted to have a response to TKI. These results need further validation. No significant financial relationships to disclose.
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Zhou Tran, Yan, Rezan Minozada, Xiaofang Cao, Henrik J. Johansson, Rui M. Branca, Brinton Seashore-Ludlow, and Lukas M. Orre. "Immediate Adaptation Analysis Implicates BCL6 as an EGFR-TKI Combination Therapy Target in NSCLC." Molecular & Cellular Proteomics 19, no. 6 (March 31, 2020): 928–43. http://dx.doi.org/10.1074/mcp.ra120.002036.

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Drug resistance is a major obstacle to curative cancer therapies, and increased understanding of the molecular events contributing to resistance would enable better prediction of therapy response, as well as contribute to new targets for combination therapy. Here we have analyzed the early molecular response to epidermal growth factor receptor (EGFR) inhibition using RNA sequencing data covering 13,486 genes and mass spectrometry data covering 10,138 proteins. This analysis revealed a massive response to EGFR inhibition already within the first 24 h, including significant regulation of hundreds of genes known to control downstream signaling, such as transcription factors, kinases, phosphatases and ubiquitin E3-ligases. Importantly, this response included upregulation of key genes in multiple oncogenic signaling pathways that promote proliferation and survival, such as ERBB3, FGFR2, JAK3, and BCL6, indicating an early adaptive response to EGFR inhibition. Using a library of more than 500 approved and experimental compounds in a combination therapy screen, we could show that several kinase inhibitors with targets including JAK3 and FGFR2 increased the response to EGFR inhibitors. Further, we investigated the functional impact of BCL6 upregulation in response to EGFR inhibition using siRNA-based silencing of BCL6. Proteomics profiling revealed that BCL6 inhibited transcription of multiple target genes including p53, resulting in reduced apoptosis which implicates BCL6 upregulation as a new EGFR inhibitor treatment escape mechanism. Finally, we demonstrate that combined treatment targeting both EGFR and BCL6 act synergistically in killing lung cancer cells. In conclusion, or data indicates that multiple different adaptive mechanisms may act in concert to blunt the cellular impact of EGFR inhibition, and we suggest BCL6 as a potential target for EGFR inhibitor-based combination therapy.
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Colella, Barbara, Mayra Colardo, Gianna Iannone, Claudia Contadini, Cristina Saiz-Ladera, Claudia Fuoco, Daniela Barilà, Guillermo Velasco, Marco Segatto, and Sabrina Di Bartolomeo. "mTOR Inhibition Leads to Src-Mediated EGFR Internalisation and Degradation in Glioma Cells." Cancers 12, no. 8 (August 13, 2020): 2266. http://dx.doi.org/10.3390/cancers12082266.

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Epidermal Growth Factor receptor (EGFR) is a tyrosine kinase receptor widely expressed on the surface of numerous cell types, which activates several downstream signalling pathways involved in cell proliferation, migration and survival. EGFR alterations, such as overexpression or mutations, have been frequently observed in several cancers, including glioblastoma (GBM), and are associated to uncontrolled cell proliferation. Here we show that the inhibition of mammalian target of Rapamycin (mTOR) mediates EGFR delivery to lysosomes for degradation in GBM cells, independently of autophagy activation. Coherently with EGFR internalisation and degradation, mTOR blockade negatively affects the mitogen activated protein/extracellular signal-regulated kinase (MAPK)/ERK pathway. Furthermore, we provide evidence that Src kinase activation is required for EGFR internaliation upon mTOR inhibition. Our results further support the hypothesis that mTOR targeting may represent an effective therapeutic strategy in GBM management, as its inhibition results in EGFR degradation and in proliferative signal alteration.
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Mink, Sheldon R., Surabhi Vashistha, Wenxuan Zhang, Amanda Hodge, David B. Agus, and Anjali Jain. "Cancer-Associated Fibroblasts Derived from EGFR-TKI–Resistant Tumors Reverse EGFR Pathway Inhibition by EGFR-TKIs." Molecular Cancer Research 8, no. 6 (June 2010): 809–20. http://dx.doi.org/10.1158/1541-7786.mcr-09-0460.

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Zhu, Yu-Sheng, Hui-Hui Zhang, Tong Wang, and Xiao-Dong Chen. "Inhibition of EGFR attenuates EGF-induced activation of retinal pigment epithelium cell via EGFR/AKT signaling pathway." International Journal of Ophthalmology 17, no. 6 (June 18, 2024): 1018–27. http://dx.doi.org/10.18240/ijo.2024.06.05.

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AIM: To explore the effect of epidermal growth factor receptor (EGFR) inhibition by erlotinib and EGFR siRNA on epidermal growth factor (EGF)-induced activation of retinal pigment epithelium (RPE) cells. METHODS: Human RPE cell line (ARPE-19 cells) was activated by 100 ng/mL EGF. Erlotinib and EGFR siRNA were used to intervene EGF treatment. Cellular viability, proliferation, and migration were detected by methyl thiazolyl tetrazolium (MTT) assay, bromodeoxyuridine (BrdU) staining assay and wound healing assay, respectively. EGFR/protein kinase B (AKT) pathway proteins and N-cadherin, α-smooth muscle actin (α-SMA), and vimentin were tested by Western blot assay. EGFR was also determined by immunofluorescence staining. RESULTS: EGF treatment for 24h induced a significant increase of ARPE-19 cells’ viability, proliferation and migration, phosphorylation of EGFR/AKT proteins, and decreased total EGFR expression. Erlotinib suppressed ARPE-19 cells’ viability, proliferation and migration through down regulating total EGFR and AKT protein expressions. Erlotinib also inhibited EGF-induced an increase of proliferative and migrative ability in ARPE-19 cells and clearly suppressed EGF-induced EGFR/AKT proteins phosphorylation and decreased expression of N-cadherin, α-SMA, and vimentin proteins. Similarly, EGFR inhibition by EGFR siRNA significantly affected EGF-induced an increase of cell proliferation, viability, and migration, phosphorylation of EGFR/AKT proteins, and up-regulation of N-cadherin, α-SMA, and vimentin proteins. CONCLUSION: Erlotinib and EGFR-knockdown suppress EGF-induced cell viability, proliferation, and migration via EGFR/AKT pathway in RPE cells. EGFR inhibition may be a possible therapeutic approach for proliferative vitreoretinopathy (PVR).
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Watanabe, Sho, Yasushi Goto, Hiroyuki Yasuda, Takashi Kohno, Noriko Motoi, Yuichiro Ohe, Hiroyoshi Nishikawa, Susumu S. Kobayashi, Kazuyoshi Kuwano, and Yosuke Togashi. "HSP90 inhibition overcomes EGFR amplification‐induced resistance to third‐generation EGFR‐TKIs." Thoracic Cancer 12, no. 5 (January 20, 2021): 631–42. http://dx.doi.org/10.1111/1759-7714.13839.

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Maron, S., S. Moya, F. Morano, M. J. Emmett, U. Disel, S. Chalasani, G. Ku, et al. "1421P EGFR inhibition in EGFR-amplified esophagogastric cancer (EGC): Retrospective global experience." Annals of Oncology 32 (September 2021): S1065—S1066. http://dx.doi.org/10.1016/j.annonc.2021.08.1530.

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Le, Tri, Joseph Sailors, Dwight H. Oliver, Melissa Mayer, Sharon Hoskin, and David E. Gerber. "Histologic transformation of EGFR mutant lung adenocarcinoma without exposure to EGFR inhibition." Lung Cancer 105 (March 2017): 14–16. http://dx.doi.org/10.1016/j.lungcan.2017.01.005.

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Runkle, Kristin B., Akriti Kharbanda, Ewa Stypulkowski, Xing-Jun Cao, Wei Wang, Benjamin A. Garcia, and Eric S. Witze. "Inhibition of DHHC20-Mediated EGFR Palmitoylation Creates a Dependence on EGFR Signaling." Molecular Cell 62, no. 3 (May 2016): 385–96. http://dx.doi.org/10.1016/j.molcel.2016.04.003.

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Pham-Danis, Catherine, Sarah Gehrke, Etienne Danis, Andrii I. Rozhok, Michael W. Daniels, Dexiang Gao, Christina Collins, José T. Di Paola, Angelo D'Alessandro, and James DeGregori. "Urea Cycle Sustains Cellular Energetics upon EGFR Inhibition in EGFR-Mutant NSCLC." Molecular Cancer Research 17, no. 6 (February 26, 2019): 1351–64. http://dx.doi.org/10.1158/1541-7786.mcr-18-1068.

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Eggermont, Carolien, Gustavo J. Gutierrez, Jacques De Grève, and Philippe Giron. "Inhibition of PLK1 Destabilizes EGFR and Sensitizes EGFR-Mutated Lung Cancer Cells to Small Molecule Inhibitor Osimertinib." Cancers 15, no. 9 (May 2, 2023): 2589. http://dx.doi.org/10.3390/cancers15092589.

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Tyrosine kinase inhibitors (TKI) targeting the epidermal growth factor receptor (EGFR) have significantly prolonged survival in EGFR-mutant non-small cell lung cancer patients. However, the development of resistance mechanisms prohibits the curative potential of EGFR TKIs. Combination therapies emerge as a valuable approach to preventing or delaying disease progression. Here, we investigated the combined inhibition of polo-like kinase 1 (PLK1) and EGFR in TKI-sensitive EGFR-mutant NSCLC cells. The pharmacological inhibition of PLK1 destabilized EGFR levels and sensitized NSCLC cells to Osimertinib through induction of apoptosis. In addition, we found that c-Cbl, a ubiquitin ligase of EGFR, is a direct phosphorylation target of PLK1 and PLK1 impacts the stability of c-Cbl in a kinase-dependent manner. In conclusion, we describe a novel interaction between mutant EGFR and PLK1 that may be exploited in the clinic. Co-targeting PLK1 and EGFR may improve and prolong the clinical response to EGFR TKI in patients with an EGFR-mutated NSCLC.
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Stitzlein, Lea, Matthew Luetzen, Caitlin McCabe, Maninder Khosla, Melissa Singh, Xiaoping Su, Yue Lu, et al. "Abstract 3329: Efficacy of EGFR/PI3K signaling inhibition is enhanced with LSD1 inhibition in glioblastoma stem cell (GSC) models." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3329. http://dx.doi.org/10.1158/1538-7445.am2022-3329.

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Abstract Mutated and dysregulated protein kinases, such as EGFR and PI3K, have become major targets in cancer therapy due to the growth advantage they confer and the frequency of alterations. In glioblastoma (GBM), EGFR and PI3K are two of the most mutated genes and result in hyperactivation of these kinases. However, single agent inhibition has offered minimal success, largely due to the development of resistance from compensatory downstream signaling pathways. One strategy to circumvent resistance and improve efficacy in GBM is to use combination therapy, such as concurrent inhibition of EGFR or PI3K with inhibition of relevant epigenetic modulators. In GBM, lysine-specific demethylase 1 (LSD1) is an important epigenetic regulator that has shown to promote kinase signaling in cancer models. Therefore, the present study sought to define the relationship between the EGFR/PI3K signaling pathway and LSD1 and to evaluate the efficacy of co-inhibition of EGFR/PI3K and LSD1 in GBM.Transcriptional changes were examined following knockdown of LSD1 in isogenic human GBM cells using RNA-seq. These data were analyzed by GSEA to evaluate biological processes associated with the LSD1 expression. We identified several kinase signaling processes that were enriched in GBM cells with wild type LSD1 such as gene sets for regulation of PI3K activity, RTK binding, and transmembrane RTK activity. The effect of kinase inhibition on LSD1 expression was assessed using western blot analysis. We also evaluated the effects of LSD1 inhibition on expression of downstream kinase signaling proteins. Three kinase inhibitors directed against either EGFR or PI3K were evaluated in GSCs as single agents and in combination with LSD1 inhibitors. The three kinase inhibitors, osimertinib, erlotinib, and BKM120, all have evidence of some brain penetrance. We also evaluated a novel dual kinase inhibitor, MTX-241, which targets both EGFR and PI3K simultaneously. Five LSD1 inhibitors were assessed for their ability to enhance efficacy of EGFR/PI3K inhibitors.Our results demonstrate that LSD1 protein expression can be modulated by stimulation of EGFR in patient-derived GSCs. We observed an increase in LSD1 protein expression following the addition of EGF in GSC 17 cells. The concurrent inhibition of EGFR/PI3K and LSD1 enhanced the in vitro efficacy compared to single agent, supporting convergence of kinase signaling and LSD1 dependent pathways. In fact, several treatment combinations of EGFR/PI3K inhibitors and LSD1 inhibitors resulted in synergistic effects in multiple GSC lines.In summary, our results highlight the need for effective therapy combinations that can reduce the population of GSCs and avoid the adaptive resistance that is typical of kinase inhibitors. Future studies will focus on evaluating the efficacy and tolerability of the most promising treatment combinations in vivo using orthotopic xenograft models of the GSCs. Citation Format: Lea Stitzlein, Matthew Luetzen, Caitlin McCabe, Maninder Khosla, Melissa Singh, Xiaoping Su, Yue Lu, Joy Gumin, Frederick Lang, Christopher Whitehead, Judith Sebolt-Leopold, Joya Chandra. Efficacy of EGFR/PI3K signaling inhibition is enhanced with LSD1 inhibition in glioblastoma stem cell (GSC) models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3329.
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Liu, Bin, Shanshan Song, Rita Setroikromo, Siwei Chen, Wenteng Hu, Deng Chen, Anthonie van der Wekken, et al. "CX Chemokine Receptor 7 Contributes to Survival of KRAS-Mutant Non-Small Cell Lung Cancer upon Loss of Epidermal Growth Factor Receptor." Cancers 11, no. 4 (March 30, 2019): 455. http://dx.doi.org/10.3390/cancers11040455.

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KRAS-driven non-small cell lung cancer (NSCLC) patients have no effective targeted treatment. In this study, we aimed to investigate targeting epidermal growth factor receptor (EGFR) as a therapeutic approach in KRAS-driven lung cancer cells. We show that ablation of EGFR significantly suppressed tumor growth in KRAS-dependent cells and induced significantly higher expression of CX chemokine receptor 7 (CXCR7) and activation of MAPK (ERK1/2). Conversely, rescue of EGFR led to CXCR7 downregulation in EGFR−/− cells. Dual EGFR and CXCR7 inhibition led to substantial reduction of MAPK (pERK) and synergistic inhibition of cell growth. Analysis of two additional EGFR knockout NSCLC cell lines using CRISPR/Cas9 revealed genotype dependency of CXCR7 expression. In addition, treatment of different cells with gefitinib increased CXCR7 expression in EGFRwt but decreased it in EGFRmut cells. CXCR7 protein expression was detected in all NSCLC patient samples, with higher levels in adenocarcinoma as compared to squamous cell lung carcinoma and healthy control cases. In conclusion, EGFR and CXCR7 have a crucial interaction in NSCLC, and dual inhibition may be a potential therapeutic option for NSCLC patients.
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Voisin, Laure, Sylvain Foisy, Edith Giasson, Chantal Lambert, Pierre Moreau, and Sylvain Meloche. "EGF receptor transactivation is obligatory for protein synthesis stimulation by G protein-coupled receptors." American Journal of Physiology-Cell Physiology 283, no. 2 (August 1, 2002): C446—C455. http://dx.doi.org/10.1152/ajpcell.00261.2001.

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The epidermal growth factor receptor (EGFR) was recently identified as a signal transducer of G protein-coupled receptors (GPCRs). In this study, we have examined the contribution of EGFR transactivation to the growth-promoting effect of GPCRs on vascular smooth muscle cells. Activation of the Gq-coupled ANG II receptor or Gi-coupled lysophosphatidic acid receptor resulted in increased tyrosine phosphorylation and activation of EGFR. Specific inhibition of EGFR kinase activity by tyrphostin AG-1478 or expression of a dominant-negative EGFR mutant abolished this response. Importantly, inhibition of EGFR function strongly attenuated the global stimulation of protein synthesis by GPCR agonists in vitro in cultured aortic smooth muscle cells and in vivo in the rat aorta and in small resistance arteries. The growth inhibition was associated with a marked reduction of extracellular signal-regulated kinase and phosphoinositide 3-kinase pathway activity and the resulting suppression of eukaryotic translation initiation factor 4E and 4E binding protein 1 phosphorylation. Our results demonstrate that EGFR transactivation is a physiologically relevant action of GPCRs linked to translational control and protein synthesis.
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Cruz-Gordillo, Peter, Megan E. Honeywell, Nicholas W. Harper, Thomas Leete, and Michael J. Lee. "ELP-dependent expression of MCL1 promotes resistance to EGFR inhibition in triple-negative breast cancer cells." Science Signaling 13, no. 658 (November 17, 2020): eabb9820. http://dx.doi.org/10.1126/scisignal.abb9820.

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Targeted therapeutics for cancer generally exploit “oncogene addiction,” a phenomenon in which the growth and survival of tumor cells depend on the activity of a particular protein. However, the efficacy of oncogene-targeted therapies varies substantially. For instance, targeting epidermal growth factor receptor (EGFR) signaling is effective in some non–small cell lung cancer (NSCLC) but not in triple-negative breast cancer (TNBC), although these cancers show a similar degree of increase in EGFR activity. Using a genome-wide CRISPR-Cas9 genetic knockout screen, we found that the Elongator (ELP) complex mediates insensitivity to the EGFR inhibitor erlotinib in TNBC cells by promoting the synthesis of the antiapoptotic protein Mcl-1. Depleting ELP proteins promoted apoptotic cell death in an EGFR inhibition–dependent manner. Pharmacological inhibition of Mcl-1 synergized with EGFR inhibition in a panel of genetically diverse TNBC cells. The findings indicate that TNBC “addiction” to EGFR signaling is masked by the ELP complex and that resistance to EGFR inhibitors in TNBC might be overcome by cotargeting Mcl-1.
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Kim, Ji Hye, Jongwook Kim, Se Seul Im, Ji Hyeon Lee, Sein Hwang, Eun-Ju Chang, Dong-Myung Shin, Jin Kyung Rho, and Jaekyoung Son. "BIX01294 inhibits EGFR signaling in EGFR-mutant lung adenocarcinoma cells through a BCKDHA-mediated reduction in the EGFR level." Experimental & Molecular Medicine 53, no. 12 (December 2021): 1877–87. http://dx.doi.org/10.1038/s12276-021-00715-7.

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AbstractBIX01294 (BIX), an inhibitor of the G9a histone methyltransferase, has been reported to have antitumor activity against a variety of cancers. However, the molecular mechanisms underlying its anticancer effects, particularly those against lung cancer, remain unclear. Here, we report that BIX induces apoptotic cell death in EGFR-mutant non-small cell lung cancer (NSCLC) cells but not in their wild-type counterparts. Treatment with BIX resulted in a significant reduction in the EGFR level and inhibition of EGFR signaling only in EGFR-mutant NSCLC cells, leading to apoptosis. BIX also inhibited mitochondrial metabolic function and decreased the cellular energy levels that are critical for maintaining the EGFR level. Furthermore, BIX transcriptionally downregulated the transcription of branched-chain α-keto acid dehydrogenase (BCKDHA), which is essential for fueling the tricarboxylic acid (TCA) cycle. Interestingly, this BCKDHA downregulation was due to inhibition of Jumanji-domain histone demethylases but not the G9a histone methyltransferase. We observed that KDM3A, a Jumonji histone demethylase, epigenetically regulates BCKDHA expression by binding to the BCKDHA gene promoter. BIX exposure also led to a significant decrease in the EGFR level, causing apoptosis in EGFR-TKI (tyrosine kinase inhibitor)-resistant cell lines, which are dependent on EGFR signaling for survival. Taken together, our current data suggest that BIX triggers apoptosis only in EGFR-mutant NSCLC cells via inhibition of BCKDHA-mediated mitochondrial metabolic function.
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Chen, Nan, and Robert C. Doebele. "Abstract 1100: miR205 mediates acquired resistance to ALK inhibition via targeting Mig6 expression and enhancing EGFR signaling." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1100. http://dx.doi.org/10.1158/1538-7445.am2022-1100.

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Abstract Complete responses to ALK tyrosine kinase inhibitors (TKIs) are rare and resistance eventually develops in ALK fusion-positive non-small cell lung cancer patients. To overcome resistance and improve therapeutic outcomes, it is crucial to understand the molecular mechanisms contributing to resistance. Our lab has previously shown EGFR signaling mediates adaptive resistance to ALK inhibitors. We demonstrated that RNA and protein levels of Mig6, an endogenous protein inhibitor of EGFR, were suppressed rapidly following ALK inhibition, thus unlocking EGFR from inhibition to support cell survival. In this study, we asked whether EGFR signaling activation and Mig6 suppression persist once acquired resistance is established. An EML4-ALK cell line, H3122, was continuously exposed to a fixed dose of the ALK inhibitor crizotinib to generate three resistant lines (H3122-CR1, -2, and -3). All H3122-CR lines lacked ALK kinase mutations and were also cross-resistant to other ALK TKIs including ceritinib and alectinib. We found phosphorylation and total EGFR were upregulated while Mig6 protein was attenuated across all resistant lines compared to their parental counterpart. Afatinib, a pan-ERBB family inhibitor, or Mig6 overexpression, was able to re-sensitize those resistant cells to ALK inhibition. Interestingly, we did not find Mig6 overexpression altered phosphorylation of EGFR. Previously reported data suggest that Mig6 competes with Shc1, a critical signaling adapter shared by ALK and EGFR, for the same substrate-binding cleft on EGFR. We then hypothesized Mig6 could block EGFR-Shc1 binding and downstream signaling transduction without directly impacting EGFR phosphorylation. Indeed, the co-immunoprecipitation assay showed Mig6 knockdown in H3122 cells enhanced Shc1 binding to EGFR without altering phosphorylation of EGFR itself, suggesting a novel mechanism in regulating EGFR signaling by impairing the signaling adapter binding. We then investigated the mechanism responsible for Mig6 protein attenuation in resistant lines. By examining the RNA-seq data for all the CR lines compared to the parental H3122, we found MIR205HG was substantially upregulated in resistant cells. MIR205HG is the host gene for miR-205, which was known to target ERRFI1 gene that encodes Mig6. Stem-loop RT-qPCR confirmed that miR-205 was increased ~5 fold in all CR lines. Overexpressing miR-205 in H3122 cells could downregulate Mig6 expression in a dose-dependent manner. Herein we presented a novel resistance mechanism to ALK inhibition by which miR205 upregulation attenuates Mig6 expression, releasing EGFR-Shc1 signaling transduction from inhibition to support cell survival. This study also provides additional support for targeting EGFR signaling to overcome ALK TKI resistance to improve patient survival. Citation Format: Nan Chen, Robert C. Doebele. miR205 mediates acquired resistance to ALK inhibition via targeting Mig6 expression and enhancing EGFR signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1100.
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42

Noch, E., I. Alnahhas, L. Palma, and L. Cantley. "P13.18 Inhibition of epidermal growth factor receptor and platelet-derived growth factor receptor-alpha exerts synergistic efficacy in glioblastoma." Neuro-Oncology 23, Supplement_2 (September 1, 2021): ii36. http://dx.doi.org/10.1093/neuonc/noab180.125.

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Abstract BACKGROUND Despite our understanding of the genetic changes that precipitate gliomagenesis, targeted therapy has failed in glioblastoma (GBM) with median survival not significantly improved over the past two decades. Epidermal growth factor receptor (EGFR) alterations, including amplification and activating mutations, are among the most common genetic changes in GBM, occurring in more than half of cases. EGFR is located on Chr. 7, and Chr. 7 gain is one of the earliest events precipitating gliomagenesis. Various EGFR inhibitors, including tyrosine kinase inhibitors, monoclonal antibodies, vaccines, and CAR-T cells have failed in GBM due to intrinsic heterogeneity and receptor tyrosine kinase bypass pathways that mediate therapeutic resistance. New targeted therapeutic approaches to leverage synergistic combinations are desperately needed to improve GBM prognosis. Using the TCGA and other GBM databases, we have previously demonstrated that the presence of PDGFRAamplification in patients with EGFR-amplified GBM carries significantly worse survival. EGFR and PDGFRA co-expression occur in more than one-third of GBM patients. The PDGFRA ligand PDGFA is also located on Chr. 7, and its expression is significantly increased with Chr. 7 gain and EGFR copy number increase. Therefore, Chr. 7 gain inherently leads to co-activation of both EGFR and PDGFRA signaling pathways. MATERIALS AND METHODS We used models of patient-derived glioblastoma cells to test combined inhibition of epidermal growth factor receptor and platelet-derived growth factor receptor-alpha in vitro. RESULTS Using patient-derived GBM models with Chr. 7 gain, we found that combined inhibition of both EGFR and PDGFRA using a variety of FDA-approved EGFR-targeted agents (Erlotinib, Gefitinib, Dacomitinib, Neratinib, and Osimertinib) and Crenolanib, respectively, leads to synergistic cytotoxicity in vitro. We found that inhibition of either EGFR or PDGFRA alone led to receptor cross-activation, and EGF and PDGF-AA-induced receptor tyrosine kinase activation was blocked by Neratinib and Crenolanib. Immunoprecipitation experiments and proximity ligation assays demonstrated that combined inhibition prevents EGFR and PDGFRA heterodimerization and pathways of therapeutic resistance. This combined inhibition led to decreased activation of downstream signaling pathways, including phosphatidylinositol 3-kinase and mitogen-activated protein kinase. CONCLUSIONS We show that combined inhibition of EGFR and PDGFRA exerts synergistic cytotoxicity in GBM and prevents resistance pathways that emerge during single-agent targeted therapy against these receptor tyrosine kinases. These pathways are targetable with FDA-approved agents that could be used in patients with GBM with Chr. 7 gain.
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Szantai-Kis, C., I. Kovesdi, D. Eros, P. Banhegyi, A. Ullrich, G. Keri, and L. Orfi. "Prediction Oriented QSAR Modelling of EGFR Inhibition." Current Medicinal Chemistry 13, no. 3 (February 1, 2006): 277–87. http://dx.doi.org/10.2174/092986706775476098.

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Mazorra, Zaima, Lisset Chao, Anabel Lavastida, Belinda Sanchez, Mayra Ramos, Normando Iznaga, and Tania Crombet. "Nimotuzumab: beyond the EGFR signaling cascade inhibition." Seminars in Oncology 45, no. 1-2 (January 2018): 18–26. http://dx.doi.org/10.1053/j.seminoncol.2018.04.008.

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Reeves, Gregory T., Rachel Kalifa, Daryl E. Klein, Mark A. Lemmon, and Stanislav Y. Shvartsman. "Computational analysis of EGFR inhibition by Argos." Developmental Biology 284, no. 2 (August 2005): 523–35. http://dx.doi.org/10.1016/j.ydbio.2005.05.013.

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Stella, Giulia M., Claudio Valizia, Michele Zorzetto, Simona Inghilleri, Adele Valentini, Roberto Dore, Sara Colombo, Francesco Valentino, Giulio Orlandoni, and Patrizia Morbini. "Unexpected responses to EGFR inhibition in NSCLC." Respiratory Medicine Case Reports 16 (2015): 32–34. http://dx.doi.org/10.1016/j.rmcr.2015.06.006.

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Swanson, Christina, and William H. Robinson. "EGFR Inhibition Ameliorates Murine Collagen-induced Arthritis." Clinical Immunology 135 (January 2010): S59. http://dx.doi.org/10.1016/j.clim.2010.03.181.

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Argiris, Athanassios. "EGFR inhibition for recurrent or metastatic HNSCC." Lancet Oncology 16, no. 5 (May 2015): 488–89. http://dx.doi.org/10.1016/s1470-2045(15)70178-6.

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Betzen, C. "EGFR-Inhibition als neuer Therapieansatz bei RPGN." Der Nephrologe 7, no. 1 (January 2012): 46–47. http://dx.doi.org/10.1007/s11560-011-0625-4.

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Liu, Na, Li Wang, Tao Yang, Chongxiang Xiong, Liuqing Xu, Yingfeng Shi, Wenfang Bao, et al. "EGFR Inhibition Alleviates Hyperuricemic Nephropathy in Rats." Hong Kong Journal of Nephrology 17, no. 2 (October 2015): S59. http://dx.doi.org/10.1016/j.hkjn.2015.09.005.

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