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Journal articles on the topic 'Herceptin resistant breast cancer'

Author: Grafiati

Published: 4 June 2021

Last updated: 1 February 2022

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1

Buiga, Elson, Tabernero, and Schwartz. "Kinetic Modeling of DUSP Regulation in Herceptin-Resistant HER2-Positive Breast Cancer." Genes 10, no. 8 (July 26, 2019): 568. http://dx.doi.org/10.3390/genes10080568.

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Background: HER2 (human epidermal growth factor 2)-positive breast cancer is an aggressive type of breast cancer characterized by the overexpression of the receptor-type protein tyrosine kinase HER2 or amplification of the HER2 gene. It is commonly treated by the drug trastuzumab (Herceptin), but resistance to its action frequently develops and limits its therapeutic benefit. Dual-specificity phosphatases (DUSPs) were previously highlighted as central regulators of HER2 signaling; therefore, understanding their role is crucial to designing new strategies to improve the efficacy of Herceptin treatment. We investigated whether inhibiting certain DUSPs re-sensitized Herceptin-resistant breast cancer cells to the drug. We built a series of kinetic models incorporating the key players of HER2 signaling pathways and simulating a range of inhibition intensities. The simulation results were compared to live tumor cells in culture, and showed good agreement with the experimental analyses. In particular, we observed that Herceptin-resistant DUSP16-silenced breast cancer cells became more responsive to the drug when treated for 72 h with Herceptin, showing a decrease in resistance, in agreement with the model predictions. Overall, we showed that the kinetic modeling of signaling pathways is able to generate predictions that assist experimental research in the identification of potential targets for cancer treatment.

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2

Choi, Michael Phillip, Alice P. Chung, Shikha Bose, Bingchen Han, Ying Qu, Xiao Zhang, Xiaojiang Cui, and Armando E. Giuliano. "The basal phenotype as a clinically relevant indicator of trastuzumab resistance in HER2+ breast cancer." Journal of Clinical Oncology 32, no. 26_suppl (September 10, 2014): 154. http://dx.doi.org/10.1200/jco.2014.32.26_suppl.154.

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154 Background: Trastuzumab (Herceptin) resistance remains a clinical challenge but the mechanism is not well understood. Recently, studies have identified a subset of Her2+ breast cancer called basal HER2 that expresses basal genes. We investigated the effect of basal gene expression on Herceptin response in HER2+ breast cancer cell lines and on prognosis in HER2+ breast cancer patients. Methods: Non-basal (BT474, SKBR3) and basal (HCC1569, HCC1954, JIMT-1) HER2+ cell lines were chosen based on basal cytokeratin expression. Cell proliferation was assessed after treatment with vehicle, Herceptin (H), Paclitaxel (P), H+P, Akt Inhibitor (AI), and H+AI. HER2 signaling was examined using immunoblotting of p-Akt and p-ERK. Because breast cancer stem cells (BCSC) are linked to basal breast tumors and treatment resistance, we assessed BCSC activity using mammosphere formation and aldehyde dehydrogenase (ALDH) positivity. Immunohistochemical staining of HER2+ breast cancers for basal markers CK5/6, CK14, and EGFR was correlated with clinicopathologic features and survival in 88 patients with Stage 1-3 HER2+ breast cancer treated with Herceptin. Results: Basal HER2 cells were resistant to Herceptin compared to non-basal HER2 cells but this resistance was overcome by Akt inhibition. Immunoblotting showed that non-basal HER2 cells had decreased p-Akt after Herceptin treatment which was not seen in basal HER2 cells. There was no difference in p-ERK levels after Herceptin therapy in all cell lines. Basal HER2 cells had increased mammosphere formation and ALDH positivity suggesting higher stem cell activity compared to non-basal HER2 cells. Of the HER2+ patients, 33/88 (37.5%) expressed at least one basal marker. Basal Her2 tumors were associated with higher grade (p = 0.04) and more ER/PR negativity (p < 0.01). CK14 expression correlated with worse overall survival by log-rank test (p = 0.02), while EGFR showed a similar trend (p = 0.06). Conclusions: Basal HER2 breast cancer cell lines have Herceptin resistance which may be due to constitutively active Akt signaling and increased stem cell activity. Clinically, basal marker expression predicts Herceptin resistance and worse outcomes in HER2+ breast cancer patients.

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3

Chen, Bin, Yuanzhong Wang, Susan E. Kane, and Shiuan Chen. "Improvement of sensitivity to tamoxifen in estrogen receptor-positive and Herceptin-resistant breast cancer cells." Journal of Molecular Endocrinology 41, no. 5 (September 3, 2008): 367–77. http://dx.doi.org/10.1677/jme-08-0026.

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ERBB2 overexpression in estrogen receptor (ER)-positive breast cancer cells such as BT474 (BT) cells has been found to confer resistance to tamoxifen, and suppression of ERBB2 improves the antiproliferative effects of tamoxifen. In this study, the responsiveness to tamoxifen in the BT/HerR, Herceptin-resistant BT cell lines established through constant Herceptin exposure, was evaluated. Compared with BT cells, improvement of sensitivity to tamoxifen in BT/HerR was demonstrated by ER functional analysis and cell proliferation assay. Tamoxifen in the resistant cell line was found to inhibit 17β-estradiol-stimulating estrogen-responsive gene pS2 expression more effectively than in BT cells in real-time PCR assay. Western blot analysis showed that cross-phosphorylation between ER and downstream components of ERBB2 was attenuated in BT/HerR cells. ER redistribution from cytoplasm to nucleus could be found in these cells through immunofluorescence and confocal studies, and importantly, chromatin immunoprecipitation studies demonstrated that tamoxifen induced occupancy of the pS2 promoter by ER and nuclear receptor corepressor (NCOR1) instead of coactivator NCOA3 in these cells. Finally, combination of tamoxifen and Herceptin was found to improve the sensitivity of BT/HerR cells to Herceptin. Our results suggest that the ER genomic pathway in the ER-positive and Herceptin-resistant breast cancer cells may be reactivated, allowing tamoxifen therapy to be effective again, and a combination of tamoxifen and Herceptin can be a potential therapeutic strategy for ER-positive and Herceptin-resistant human breast cancer.

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4

Lai, Hung-Wen, Su-Yu Chien, Shou-Jen Kuo, Ling-Ming Tseng, Hui-Yi Lin, Chin-Wen Chi, and Dar-Ren Chen. "The Potential Utility of Curcumin in the Treatment of HER-2-Overexpressed Breast Cancer: AnIn VitroandIn VivoComparison Study with Herceptin." Evidence-Based Complementary and Alternative Medicine 2012 (2012): 1–12. http://dx.doi.org/10.1155/2012/486568.

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HER-2 is an important oncoprotein overexpressed in about 15–25% of breast cancers. We hypothesized that the ability of curcumin to downregulate HER-2 oncoprotein and inhibit the signal transduction pathway of PI3K/Akt, MAPK, and NF-κB activation may be important in the treatment of HER-2-overexpressed breast cancer. To examine the effect of curcumin on breast cancer cells, MCF-7, MDA-MB-231, MCF-10A, BT-474, and SK-BR-3-hr (a herceptin resistant strain from SK-BR-3) cells were used forin vitroanalysis. Thein vivoeffect of curcumin on HER-2-overexpressed breast cancer was investigated with the HER-2-overexpressed BT-474 xenograft model. Cell growth, cell cycle change, the antimobility effect, signal transduction, and xenograft volume analysis between groups treated with herceptin and/or curcumin were tested. Curcumin decreased the cell growth of various breast cancer cell lines (MCF-7, MDA-MB-231, MCF-10A, BT-474, and SK-BR-3-hr). In Western blot analysis, the phosphorylation of Akt, MAPK, and expression of NF-κB were reduced in BT-474 cells, but not in SK-BR-3-hr cells, after treatment with herceptin. When treated with curcumin, the HER-2 oncoprotein, phosphorylation of Akt, MAPK and expression of NF-κB were decreased in both BT-474 and SK-BR-3-hr cells. In the BT-474 xenograft model, though not as much as herceptin, curcumin did effectively decrease the tumor size. The combination of curcumin with herceptin was not better than herceptin alone; however, the combination of taxol and curcumin had an antitumor effect comparable with taxol and herceptin. The results suggested that curcumin has potential as a treatment for HER-2-overexpressed breast cancer.

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5

Crawford, Anatasha, and Rita Nahta. "Targeting Bcl-2 in Herceptin-Resistant Breast Cancer Cell Lines." Current Pharmacogenomics and Personalized Medicine 9, no. 3 (September 1, 2011): 184–90. http://dx.doi.org/10.2174/187569211796957584.

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6

Kute, Timothy, Christopher M. Lack, Mark Willingham, Bimjhana Bishwokama, Holly Williams, Kathy Barrett, Tanita Mitchell, and James P. Vaughn. "Development of Herceptin resistance in breast cancer cells." Cytometry 57A, no. 2 (2004): 86–93. http://dx.doi.org/10.1002/cyto.a.10095.

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7

Yuan, Yuan, Huanyao Gao, Yongxian Zhuang, Lixuan Wei, Jia Yu, Zhe Zhang, Lili Zhang, and Liewei Wang. "NDUFA4L2 promotes trastuzumab resistance in HER2-positive breast cancer." Therapeutic Advances in Medical Oncology 13 (January 2021): 175883592110278. http://dx.doi.org/10.1177/17588359211027836.

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Background: Trastuzumab (Herceptin) is the key systemic therapy for HER2-positive breast cancer. However, the initial response rate is limited to approximately 50% in patients. Moreover, most patients, especially at an advanced stage, eventually develop acquired resistance. Understanding the mechanisms of trastuzumab resistance is crucial for achieving better treatment outcome in this group of patients. Methods: A trastuzumab-resistant (TR) cell line was developed using the BT474 HER2-positive breast cancer cell line. Whole-transcriptome expression array was performed and the TR-related gene NDUFA4L2 was identified by differential expression analysis between BT474 and BT474-TR. Mitochondrial localization of NDUFA4L2 was confirmed by immunofluorescence and western blotting using mitochondrial fractionation. Mitochondrial function and energy metabolism were evaluated using Seahorse, ATP production, and lactate production assays, and cellular reactive oxygen species (ROS) levels were determined using DCFDA. NDUFA4L2 expression in patients was evaluated by immunohistochemistry, and relapse-free survival was analyzed using the Kaplan–Meier method. Results: NDUFA4L2 was highly expressed in the TR HER2-positive breast cancer cell line. High expression level of NDUFA4L2 was associated with shorter relapse-free intervals in trastuzumab-treated HER2-positive breast cancer patients. Overexpression of NDUFA4L2 enhanced Warburg effects, enhanced aerobic glycolysis, reduced oxygen consumption, and lowered ROS production. Mechanistically, overexpression of NDUFA4L2 facilitated mitochondrial relocalization of HER2 and suppressed ROS production, thus rendering cancer cells more resistant to trastuzumab treatment. Conclusions: We identified NDUFA4L2 as a new biomarker and potential therapeutic target for TR HER2-positive breast cancer.

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8

Eitler, Jiri, Natalie Wotschel, Nicole Miller, Laurent Boissel, Hans G. Klingemann, Winfried Wels, and Torsten Tonn. "Inability of granule polarization by NK cells defines tumor resistance and can be overcome by CAR or ADCC mediated targeting." Journal for ImmunoTherapy of Cancer 9, no. 1 (January 2021): e001334. http://dx.doi.org/10.1136/jitc-2020-001334.

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BackgroundOn encountering a susceptible target, natural killer (NK) cells mediate cytotoxicity through highly regulated steps of directed degranulation. Cytotoxic granules converge at the microtubule organizing center and are polarized toward the immunological synapse (IS), followed by granule exocytosis. NK cell retargeting by chimeric antigen receptors (CARs) or mAbs represents a promising strategy for overcoming tumor cell resistance. However, little is known about the lytic granule dynamics of such retargeted NK cells toward NK-cell-resistant tumors.MethodsHere, we used spinning disk confocal microscopy for live-cell imaging to analyze granule-mediated NK cell cytotoxicity in ErbB2-targeted CAR-expressing NK-92 cells (NK-92/5.28.z) and high-affinity FcR transgenic NK-92 cells plus Herceptin toward ErbB2-positive breast cancer cells (MDA-MB-453), which are resistant to parental NK-92.ResultsUnmodified NK-92 cells cocultured with resistant cancer cells showed stable conjugate formation and granule clustering, but failed to polarize granules to the IS. In contrast, retargeting by CAR or FcR+Herceptin toward the MDA-MB-453 cells enabled granule polarization to the IS, resulting in highly effective cytotoxicity. We found that in NK-92 the phosphoinositide 3-kinase pathway was activated after contact with resistant MDA-MB-453, while phospholipase C-γ (PLCγ) and mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) were not activated. In contrast, retargeting by CAR or antibody-dependent cell-mediated cytotoxicity (ADCC) provided the missing PLCγ and MEK/ERK signals.ConclusionsThese observations suggest that NK cells can create conjugates with resistant cancer cells and respond by granule clustering, but the activation signals are insufficient to induce granule polarization and consequent release of lytic enzymes. Retargeting by CAR and/or the FcR/mAb (ADCC) axis provide the necessary signals, leading to granule polarization and thereby overcoming tumor cell resistance.Keywords: NK cells, NK-92, haNK, ADCC, Chimeric Antigen Receptor (CAR), breast cancer, cancer immunotherapy, live-cell imaging, granule polarization

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9

Lu, Jianguo, Jun Pu, Xiaozhao Lu, Haiyan Fu, Mengying Wei, and Guodong Yang. "β-Diketone modified trastuzumab: A next-generation of Herceptin for resistant breast cancer cells?" Medical Hypotheses 79, no. 5 (November 2012): 602–4. http://dx.doi.org/10.1016/j.mehy.2012.07.030.

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10

Buiga, Petronela, Ari Elson, Lydia Tabernero, and Jean-Marc Schwartz. "Modelling the role of dual specificity phosphatases in herceptin resistant breast cancer cell lines." Computational Biology and Chemistry 80 (June 2019): 138–46. http://dx.doi.org/10.1016/j.compbiolchem.2019.03.018.

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11

Albrecht, Huguette. "Trastuzumab (Herceptin®): overcoming resistance inHER2-overexpressing breast cancer models." Immunotherapy 2, no. 6 (November 2010): 795–98. http://dx.doi.org/10.2217/imt.10.71.

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12

YangKolodji, Gloria Wangrong, Arjun Mehta, Mike J. Gray, and Debu Tripathy. "Phosphorylated ribosomal S6 (p-S6) as an indicator of HER2 signaling targeted drug resistance." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 609. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.609.

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609 Background: Thetargeting of HER2/neu oncoprotein with trastuzumab (Herceptin) has altered the natural history of HER2+ breast cancer, however, its clinical benefit is limited by de novo and/or acquired resistance which almost always develops in the advanced setting. While several mechanisms of resistance have been postulated, none are validated for clinical use to best select patients for treatment. Our study aims were to identify predictive biomarkers based on reproducible differences in HER2 initiated signaling pathway observed in trastuzumab-resistant, HER2-overexpressing human breast cell line models. Methods: Exposing HER2+ breast cancer cells BT474 and SKBR3 to 200 µg/ml of trastuzumab for 12 months, we established two trastuzumab-resistant, HER2 overexpressing breast cancer models BtRT and SkRT. MTT assay was used to characterize drug sensitivities of the cells. Immunocytochemistry and immunoblotting were used to assess the expression levels of HER2 signaling pathway proteins. The impact of trastuzumab on cell cycle process was analyzed by FACS. EdU incorporation was adapted to measure cell proliferation. Results: Trastuzumab-resistant cells had a higher proliferation rate and altered expression levels of HER2 signaling pathway proteins such as p-mTOR, p-S6k1, p-Akt, p-S6, and p-4EBP1, in comparison with parental cell lines. A downstream effector of HER2/Akt/mTOR pathway, phosphorylated ribosomal protein S6 (p-S6), was highly expressed and could not be suppressed by trastuzumab in the resistant cells. When the resistant cells were treated with selected HER2/Akt/mTOR pathway targeted drugs including lapatinib, erlotinib, linsitinib, AZD2014, MK-2206, everolimus and BEZ235, the level of p-S6 in these cells was found to be inversely correlated to the drug induced growth inhibition of these cells. Conclusions: p-S6 is a feasible and easy to measure molecular readout of HER2-targeted therapy resistance. This marker is a good candidate for further clinical validation to predict or efficiently measure a patient’s response to HER2/Akt/mTOR targeted drugs and to test novel agents that would reverse resistance and improve the outcome of trastuzumab refractory, HER2 overexpressing breast cancer.

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13

Vishwanatha, J. K., and P. Chaudhary. "Inhibition of triple negative and herceptin-resistant breast cancer proliferation and migration by annexin A2 antibodies." Annals of Oncology 26 (May 2015): iii29. http://dx.doi.org/10.1093/annonc/mdv120.02.

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14

Kingston, Belinda, and Stephen Johnston. "Novel Treatments in Breast Cancer." Clinical Medicine Insights: Therapeutics 8 (January 2016): CMT.S18492. http://dx.doi.org/10.4137/cmt.s18492.

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New therapies are changing the outlook for breast cancer worldwide. Breast cancer is traditionally divided into hormone receptor-positive, HER2-positive, and triple-negative disease. We have seen the development of new drugs targeting each of these breast cancer groups with promising results. In this article, the novel treatments are discussed with reference to recent clinical trial data. In each group, treatments are emerging that have had positive results in clinical trials. We discuss the new therapies aimed at evading hormone resistance in hormone receptor-positive disease, which have substantially increased the disease-free survival of patients with metastatic breast cancer in clinical trials. We have also seen multiple new therapies targeting HER2 receptors, working synergistically with Herceptin leading to dramatic and durable disease responses. Finally, in triple-negative disease, we are starting to see the results of trials using immunotherapy. Across all the treatment groups, we have seen the emergence of new therapies that are specifically designed to target the molecular drivers of an individual's cancer, regardless of hormone or HER2 positivity. This is paving the way for a more personalized approach to breast cancer treatment.

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Esparís-Ogando, A., R. Rodríguez-Barrueco, J. Borges, L. Ferreira, A. Pandiella, and A. Ocana. "Insulin-like growth factor-I receptor kinase inhibitor NVP-AEW541 is active in breast cancer cells and enhances growth inhibition by herceptin through an increase in cell cycle arrest." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 21077. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.21077.

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21077 Background: Targeting ErbB2 with the monoclonal antibody trastuzumab (Herceptin) has shown to be active in breast cancer. However, a proportion of patients do not benefit from this treatment due to primary resistance. Mechanisms proposed for this resistance include activation of other receptors involved in proliferation as is the case of the insulin-like growth factor receptor (IGF-1R).Different strategies have been proposed for the inhibition of IGF-1R such as antibodies or small tyrosine-kinase inhibitors. In this study we analyzed the mechanism of action and the antiproliferative activity of an specific IGF-1R tyrosine-kinase inhibitor termed NVP-AEW541 alone and in combination with Herceptin. Methods: MCF7, SKBR3, BT474, and MDA-MB-231 breast cancer cells were used for this study. Proliferation and apoptosis were analyzed by MTT uptake assays or Annexin-V-FITC, respectively. The levels of different signalling proteins were analyzed by Western blotting. Microarray studies were performed using the HU-133A oligonucleotide arrays (Affymetrix, Santa Clara, CA). Real time quantitative PCR was used to confirm the differentially regulated genes. Results: The IGF-1R was expressed in all the cell lines studied. Exogenous addition of IGF-1 increased the tyrosine phosphorylation of IGF-1R, and this was prevented by preincubation with NVP- AEW541. The latter also decreased MTT uptake, and provoked a slight increase in apoptosis of BT474 cells. Combination of NVP-AEW541 and Herceptin had a synergistic effect on the inhibition of BT474 proliferation. Cell cycle analyses indicated that the combined addition of NVP- AEW541 and Herceptin increased the number of cells in the G0/G1 phases. These data were complemented with an increase in p27 levels upon treatment with both compounds. Microarray analyses identified several genes whose expression was modified by each agent alone and by the combination. Conclusions: Our results indicate that the combined targeting of two receptor tyrosine kinases known to play important roles in tumor cell proliferation may be more efficient than individual targeting of these receptors. No significant financial relationships to disclose.

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Fessler, Shawn P., Mark T. Wotkowicz, Sanjeev K. Mahanta, and Cynthia Bamdad. "MUC1* is a determinant of trastuzumab (Herceptin) resistance in breast cancer cells." Breast Cancer Research and Treatment 118, no. 1 (May 5, 2009): 113–24. http://dx.doi.org/10.1007/s10549-009-0412-3.

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Chaudhary, P., S. I. Thamake, P. Shetty, and J. K. Vishwanatha. "Inhibition of triple-negative and Herceptin-resistant breast cancer cell proliferation and migration by Annexin A2 antibodies." British Journal of Cancer 111, no. 12 (October 16, 2014): 2328–41. http://dx.doi.org/10.1038/bjc.2014.542.

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Kim, Wes E., Binbin Yue, and Ginette Serrero. "Signaling Pathway of GP88 (Progranulin) in Breast Cancer Cells: Upregulation and Phosphorylation of c-myc by GP88/Progranulin in Her2-Overexpressing Breast Cancer Cells." Breast Cancer: Basic and Clinical Research 9s2 (January 2015): BCBCR.S29371. http://dx.doi.org/10.4137/bcbcr.s29371.

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Her2 is a receptor tyrosine kinase overexpressed in 25% of breast tumors. We have shown that the 88 kDa autocrine growth and survival factor GP88 (progranulin) stimulated Her2 phosphorylation and proliferation and conferred Herceptin resistance in Her2-overexpressing cells. Herein, we report that GP88 stimulates c-myc phosphorylation and upregulates c-myc levels in Her2-overexpressing cells. c-myc phosphorylation and upregulation by GP88 were not observed in non-Her2-overexpressing breast cancer cells. c-myc activation was inhibited upon treatment with ERK, PI3 kinase, and c-src pathway inhibitors, U0126, LY294002, and PP2. GP88 also stimulated c-src phosphorylation, a known upstream regulator of c-myc. Thus, we describe here a signaling pathway for GP88 in Her2-overexpressing cells, with GP88 stimulating Src phosphorylation, followed by phosphorylation and upregulation of c-myc. These data would suggest that targeting GP88 could provide a novel treatment approach in breast cancer.

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Duffy, Michael J. "Predictive Markers in Breast and Other Cancers: A Review." Clinical Chemistry 51, no. 3 (March 1, 2005): 494–503. http://dx.doi.org/10.1373/clinchem.2004.046227.

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Abstract Background: Unpredictable efficacy and toxicity are hallmarks of most anticancer therapies. Predictive markers are factors that are associated with response or resistance to a particular therapy. Methods: The English literature relating to predictive markers in oncology was reviewed. Particular attention was paid to metaanalyses, systematic reviews, prospective trials, and guidelines issued by expert panels. Results: The prototype predictive tests in oncology are the estrogen receptor (ER) and progesterone receptor (PR), which are used to select patients with breast cancer likely to respond to hormone therapy. A more recently introduced predictive marker is HER-2 for selecting patients with advanced breast cancer for treatment with the therapeutic antibody trastuzumab (Herceptin). In adjuvant breast cancer, overproduction of HER-2 may also indicate an enhanced sensitivity to high-dose anthracycline-based regimens. On the other hand, in both early and advanced breast cancer, high concentrations of HER-2 appear to correlate with a lower probability of response to hormone therapy. Although many different anticancer drugs appear to mediate tumor regression by inducing apoptosis, there is currently no consistent evidence that any of the molecules implicated in this process can be used as predictive markers. Conclusions: Currently, the only recommended predictive markers in oncology are ER and PR for selecting endocrine-sensitive breast cancers and HER-2 for identifying breast cancer patients with metastatic disease who may benefit from trastuzumab. For malignancies other than breast cancers, validated predictive markers do not exist at present.

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Ritter, C. A., R. Bianco, T. Dugger, J. Forbes, S. Qu, C. Rinehart, W. King, and C. L. Arteaga. "Mechanisms of resistance development against trastuzumab (Herceptin) in an in vivo breast cancer model." Int. Journal of Clinical Pharmacology and Therapeutics 42, no. 11 (November 1, 2004): 642–43. http://dx.doi.org/10.5414/cpp42642.

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Shetty, Praveenkumar K., Sanjay I. Thamake, Swati Biswas, Sonny L. Johansson, and Jamboor K. Vishwanatha. "Reciprocal Regulation of Annexin A2 and EGFR with Her-2 in Her-2 Negative and Herceptin-Resistant Breast Cancer." PLoS ONE 7, no. 9 (September 5, 2012): e44299. http://dx.doi.org/10.1371/journal.pone.0044299.

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Knowlden, Janice M., Iain R. Hutcheson, Helen E. Jones, Tracieann Madden, Julia M. W. Gee, Maureen E. Harper, Denise Barrow, Alan E. Wakeling, and Robert I. Nicholson. "Elevated Levels of Epidermal Growth Factor Receptor/c-erbB2 Heterodimers Mediate an Autocrine Growth Regulatory Pathway in Tamoxifen-Resistant MCF-7 Cells." Endocrinology 144, no. 3 (March 1, 2003): 1032–44. http://dx.doi.org/10.1210/en.2002-220620.

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The development of acquired resistance to antihormonal agents in breast cancer is a major therapeutic problem. We have developed a tamoxifen-resistant (TAM-R) MCF-7 breast cancer cell line to investigate the mechanisms behind this condition. Both epidermal growth factor receptor (EGFR) and c-erbB2 mRNA and protein expression were increased in TAM-R compared with wild-type MCF-7 cells, whereas comparable levels of c-erbB3 mRNA and protein were expressed in both cell lines. Under basal conditions, phosphorylated EGFR/c-erbB2, EGFR/c-erbB3 but not c-erbB2/c-erbB3 receptor heterodimers were detected in TAM-R cells in association with increased levels of phosphorylated extracellular-signal regulated kinase 1/2 (ERK1/2). Both cell lines were capable of generating a range of EGFR-specific ligands and increased expression of transforming growth factor α was observed in TAM-R cells. Treatment of TAM-R cells with ZD1839 (Iressa) or trastuzumab (Herceptin) blocked c-erbB receptor heterodimer formation and phosphorylation, reduced ERK1/2 activity, and strongly inhibited cell growth. The MAPK kinase inhibitor PD098059 specifically reduced phosphorylated ERK1/2 levels and inhibited TAM-R growth. All three agents abolished ERK1/2 activity in wild-type cells but caused only small reductions in cell proliferation. These results demonstrate that TAM-R MCF-7 cell growth is mediated by the autocrine release and action of an EGFR-specific ligand inducing preferential EGFR/c-erbB2 dimerization and downstream activation of the ERK pathway.

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Bapat, Priyanka, Mallory Boylan, Everardo Cobos, and Julian E. Spallholz. "Cytotoxic Effects of Seleno-Trastuzumab, Trastuzumab (Herceptin) and T-DM-1 (Kadcyla) on Trastuzumab Resistant JIMT-1 Breast Cancer Cells." Free Radical Biology and Medicine 76 (November 2014): S132. http://dx.doi.org/10.1016/j.freeradbiomed.2014.10.213.

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Lin, Jiun-Han, Ching-Hwa Tsai, Jan-Show Chu, Jeou-Yuan Chen, Kenzo Takada, and Jin-Yuh Shew. "Dysregulation of HER2/HER3 Signaling Axis in Epstein-Barr Virus-Infected Breast Carcinoma Cells." Journal of Virology 81, no. 11 (March 21, 2007): 5705–13. http://dx.doi.org/10.1128/jvi.00076-07.

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ABSTRACT The role of Epstein-Barr virus (EBV) in the pathogenesis of breast cancer has been of long-standing interest to the field. Breast epithelial cells can be infected by EBV through direct contact with EBV-bearing lymphoblastoid cells, and EBV infection has recently been shown to confer breast cancer cells an increased resistance to chemotherapeutic drugs. In this study, we established EBV-infected breast cancer MCF7 and BT474 cells and demonstrated that EBV infection promotes tumorigenic activity of breast cancer cells. Firstly, we showed that the EBV-infected MCF7-A and BT474-A cells exhibited increased anchorage-independent growth in soft agar. The increased colony formation capacity in soft agar was associated with increased expression and activation of HER2/HER3 signaling cascades, as evidenced by the findings that the treatment of HER2 antibody trastuzumab (Herceptin), phosphatidylinositol 3-kinase inhibitor, or MEK inhibitor completely abolished the tumorigenic capacity. In the EBV-infected breast cancer cells, the expression of EBV latency genes including EBNA1, EBER1, and BARF0 was detected. We next showed that BARF0 alone was sufficient to efficiently up-regulate HER2/HER3 expression and promoted tumorigenic activity in MCF7 and BT474 cells by the use of both overexpression and small interfering RNA knock-down. Collectively, we demonstrated that EBV-encoded BARF0 promotes the tumorigenic activity of breast cancer cells through activation of HER2/HER3 signaling cascades.

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Huang, Xiaoping, Lizhi Gao, Shuiliang Wang, James L. McManaman, Ann D. Thor, XiaoHe Yang, Francisco J. Esteva, and Bolin Liu. "Heterotrimerization of the Growth Factor Receptors erbB2, erbB3, and Insulin-like Growth Factor-I Receptor in Breast Cancer Cells Resistant to Herceptin." Cancer Research 70, no. 3 (January 26, 2010): 1204–14. http://dx.doi.org/10.1158/0008-5472.can-09-3321.

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Serrero, G., K. Tkaczuk, N. Tait, O. Golubeva, H. Dai, F. S. Feldman, and L. Jones. "Circulating levels of the breast cancer growth factor GP88 in the serum of breast cancer (BC) patients." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 20050. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.20050.

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20050 Background: The 88 kDa autocrine growth factor PC-Cell Derived Growth Factor (GP88) plays a critical role in breast tumorigenesis. GP88 expression was low in estrogen receptor positive cells, whereas in ER negative cells, it was constitutively overexpressed. Increased GP88 expression was associated with anti-estrogen therapy resistance in ER+ cells and Herceptin resistance in Her-2 overexpressing breast tumors. Antisense inhibition of GP88 expression in human breast adenocarcinoma lead to inhibition of tumor growth in vivo. Immunohistochemical studies have shown that GP88 was expressed in 80% of invasive ductal carcinomas in correlation with expression of poor prognosis markers whereas normal tissues and benign breast lesions were negative. Since GP88 is secreted by breast cancer cells, we examined whether GP88 was found in the circulation at an elevated level in the sera of breast cancer patients when compared to healthy individuals. Methods: A blood sampling study was conducted to determine the serum level of GP88 in healthy volunteers (HV) and breast cancer patients (BC pts). Ten ml of blood was drawn every three months to obtain serum. GP88 serum concentration was determined in triplicate by quantitative enzyme immunoassay using human GP88 as standard. 126 BC pts were accrued. . In addition, sera from 53 healthy volunteers were obtained to establish a GP88 baseline in HV. BC pts characteristics: race: Caucasian- 61, African American-60, Asian-5; median age: 52.5 (range 26–84), stage I-32, II-34, III-18, IV-42. Results: Circulating GP88 was measurable in the serum. Median level of GP88 was 32.8 ng/ml (range 15.3–42.8) in HV and 43.8 ng/ml (range 15.4–158.4) in BC pts, (p-value = 0.0007). Conclusions: GP88 is measurable in the sera of HV and BC pts. Comparison between the two groups indicates that GP88 level is significantly higher in the sera of BC pts. These studies are important since it identifies GP88 as a measurable biomarker that is also a therapeutic target of malignant transformation or malignant progression of breast carcinoma (BC). Future studies will examine the correlation of GP88 level with BC prognostic factors. Correlation between the serum level of GP88 and therapeutic response to systemic therapy in breast cancer patients will also be assessed. [Table: see text]

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Cheng, Tzu-Chun, Li-Ching Chen, and Yuan-Soon Ho. "The mechanisms of histamine N-methyltransferase (HNMT)-mediated Herceptin® drug-resistance in breast cancer cells." Free Radical Biology and Medicine 108 (July 2017): S33. http://dx.doi.org/10.1016/j.freeradbiomed.2017.04.132.

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Slavin, Shimon. "Potential elimination of multi-drug resistant cancer cells by targeted non-engrafting intentionally mismatched activated donor lymphocytes." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e14007-e14007. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e14007.

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e14007 Background: Immunotherapy by targeted autologous T cells, TIL or CAR-T, are considered most effective modalities for treatment of otherwise resistant cancer, yet cure is rarely achieved. In contrast, cure of resistant disease by donor lymphocyte infusion (DLI) following allogeneic stem cell transplantation suggests that alloreactive lymphocytes represent a most effective approach for elimination of resistant malignant cells. The first patient relapsing following supra-lethal chemoradiotherapy is alive & well > 34 years. Using murine B cell leukemia (BCL1) and metastatic breast cancer (4T1) we proved that non-engrafting intentionally mismatched lymphocytes activated with IL-2 that were consistently rejected cured otherwise lethal cancer with no graft-vs-host disease (GVHD). Methods: We first applied graft-vs-tumor effects by non-engrafting Intentionally Mismatched Activated Killers (IMAK) following mild immunosuppressive conditioning to maximize homeostatic proliferation of activated T & NK cells. IMAK was first applied inpatients with multiple myeloma and lymphoma treated with donor lymphocytes pre-activated in vitro prior to infusion and for 5 days following infusion withlow dose IL-2.We next studied feasibility of Allogeneic Targeted Activated Cancer Killer cells (ATACK) using IL-2 activated haploidentical donor lymphocytes including T & NK cells targeted against antigens over-expressed on the surface of malignant cells: Her-2/neu, EGFR, VEGF and CD20 using commercially available Herceptin, Erbitux, Avastin or Rituximab, respectivelyin a pilot study involving 16 patients with advanced metastatic solid tumors. Results: Using IMAK donor lymphocytes were uniformly rejected and no patient developed GVHD. Disease-free survival > 20 years was documented in our first myeloma patient with plasmacytomas and in another relapsing after autologous SCTand in 2 patients with non-Hodgkin lymphoma. Longterm progression-free survival was reported in 5 of 31 patients with resistant solid tumors. Following ATACK transient mild toxicity was manageable in outpatient clinic and no GVHD developed. Conclusions: Using ATACK against minimal residual disease accomplishable by most cancer patients following conventional 1st line treatment may result in cure of otherwise resistant cancer while avoiding GVHD.

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Chan, Carmel T., Marianne Z. Metz, and Susan E. Kane. "Differential sensitivities of trastuzumab (Herceptin®)-resistant human breast cancer cells to phosphoinositide-3 kinase (PI-3K) and epidermal growth factor receptor (EGFR) kinase inhibitors." Breast Cancer Research and Treatment 91, no. 2 (May 2005): 187–201. http://dx.doi.org/10.1007/s10549-004-7715-1.

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Li, Hu, Xiao Zhang, Zhenyi Xu, Lingrui Li, Wenchao Liu, Zhenyu Dai, Zhongrun Zhao, Lili Xiao, Hongfeng Li, and Chaohong Hu. "Preclinical evaluation of MRG002, a novel HER2-targeting antibody-drug conjugate with potent antitumor activity against HER2-positive solid tumors." Antibody Therapeutics 4, no. 3 (July 2021): 175–84. http://dx.doi.org/10.1093/abt/tbab017.

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Abstract Background ERBB2 is a proto-oncogene of multiple cancers including breast and gastric cancers with HER2 protein overexpression or gene amplification and has been proven clinically as a valid target for these cancers. HER2-targeting agents such as Herceptin®, Kadcyla® and ENHERTU® have been approved by the FDA for the treatment of breast cancer, but these drugs still face the challenge of acquired resistance and/or severe adverse reactions in clinical use. Therefore, there is significant unmet medical need for developing new agents that are more effective and safer for patients with advanced HER2-positive solid tumors including breast and gastric cancers. Methods We report here the making of MRG002, a novel HER2-targeted antibody drug conjugate (ADC), and preclinical characterization including pharmacology, pharmacodynamics and toxicology and discuss its potential as a novel agent for treating patients with HER2-positive solid tumors. Results MRG002 exhibited similar antigen binding affinity but much reduced antibody-dependent cellular cytotoxicity (ADCC) activity compared to trastuzumab. In addition to potent in vitro cytotoxicity, MRG002 showed tumor regression in both high- and medium-to-low HER2 expressing in vivo xenograft models. Furthermore, MRG002 showed enhanced antitumor activity when used in combination with an anti-PD-1 antibody. Main findings from toxicology studies are related to the payload and are consistent with literature report of other ADCs with monomethyl auristatinE. Conclusion MRG002 has demonstrated a favorable toxicity profile and potent antitumor activities in the breast and gastric PDX models with varying levels of HER2 expression, and/or resistance to trastuzumab or T-DM1. A phase I clinical study of MRG002 in patients with HER2-positive solid tumors is ongoing (CTR20181778).

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Gu, Long, Sarah Waliany, and Susan E. Kane. "Darpp-32 and Its Truncated Variant t-Darpp Have Antagonistic Effects on Breast Cancer Cell Growth and Herceptin Resistance." PLoS ONE 4, no. 7 (July 13, 2009): e6220. http://dx.doi.org/10.1371/journal.pone.0006220.

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Davies, Angela M., Philip C. Mack, Primo N. Lara, Derick H. Lau, Kathleen Danenberg, Paul H. Gumerlock, and David R. Gandara. "Predictive Molecular Markers: Has the Time Come for Routine Use in Lung Cancer?" Journal of the National Comprehensive Cancer Network 2, no. 2 (March 2004): 125–31. http://dx.doi.org/10.6004/jnccn.2004.0011.

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Although some evidence exists to support the use of clinical factors such as performance status and weight loss to predict response and toxicity to therapy in non-small cell lung cancer (NSCLC) patients, researchers have shown little prospective data on the use of molecular markers to facilitate selection of specific chemotherapy or new molecularly targeted agents in this patient population. Breast cancer exemplifies the growing role that molecular markers are playing, not only as prognostic factors, but also in predicting response to targeted treatments such as hormonal therapy, and more recently, trastuzumab (Herceptin). Although several studies have examinedmolecular markers in lung cancer and have shown promising potential value, these studies were retrospective and require prospective validation. To identify molecular markers that reliably predict response and to be able to individualize cytotoxic and targeted therapy for NSCLC patients are the ultimate goals of future trials. This article focuses on a selected number of promising markers under study in lung cancer, including those thought to play roles in response to DNA damaging chemotherapy (excision repair cross-complementing [ERCC1], xeroderma pigmentosum group D [XPD]), taxane resistance (-tubulin III), antimetabolite therapy (RRM1), irinotecan metabolism (UGT1A1) and epidermal growth factor receptor (EGFR) pathway inhibition. To date, none of these markers can be recommended for routine use in clinical practice.

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Serrero, G., K. Tkaczuk, M. Zhan, N. Tait, C. Ilan, D. Eklund, and B. Yue. "Association of serum levels of the growth factor GP88 with disease progression in breast cancer patients." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e22021-e22021. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e22021.

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e22021 Background: The autocrine growth factor GP88 is an important player in breast cancer. GP88 is expressed in human BC tumors in correlation with their tumorigenicity. Increased GP88 expression was associated with anti-estrogen therapy resistance in ER+ cells and Herceptin resistance in Her-2 overexpressing breast tumors. Inhibition of GP88 expression inhibited tumor incidence and growth in nude mice. Immunohistochemical studies have shown that GP88 is expressed in invasive ductal carcinomas (IDC) and that high GP88 expression correlated with increased recurrence and mortality. Since GP88 is found in serum, we hypothesized that GP88 was elevated in the sera of breast cancer patients compared to healthy individuals and that GP88 serum level increases with disease progression. Methods: An IRB approved prospective study was established at the University of Maryland Breast Clinic to determine the serum level of GP88 in breast cancer patients (BC pts). Approximately 5 ml of blood was drawn every three months. GP88 serum concentration was determined in triplicate by human GP88 enzyme immunoassay. 190 BC pts were accrued. Sera from healthy volunteers (HV) were obtained to establish GP88 baseline. BC patient characteristics: Caucasian- 91, African American-92, Asian-6; median age, 51 (range 29- 86), stage I - 48, II - 52, III - 26, IV - 63. Results: Median serum GP88 level was 28.7 ng/ml (range 16.6–38.2) in HV, 40.7 ng/ml (range 6.4–100) in early stage (stage 1 -3) BC pts (p- value = 0.007) and 45.3 ng/ml (range 9.8 to 158.4) in stage 4 BC patients (p- value= 0.0007). Statistically significant increase in serum GP88 level was found in early stages as well as in metastatic disease when compared to HV. In addition, patients that were initially diagnosed with early stage disease but recurred showed a 5 to 10 fold increase in their GP88 serum levels. Conclusions: GP88 serum level is significantly higher in the sera of BC than HV subjects. Moreover, GP88 serum level increased in association with disease recurrence and progression. This study identifies GP88 as a measurable biomarker for disease progression not only at the tissue but also at the serum level. These results are also interesting since GP88 is also a therapeutic target of malignant progression of breast carcinoma. No significant financial relationships to disclose.

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Anastasi, Sergio, Gianluca Sala, Chen Huiping, Elisabetta Caprini, Giandomenico Russo, Stefano Iacovelli, Fabiana Lucini, Sigurdur Ingvarsson, and Oreste Segatto. "Loss of RALT/MIG-6 expression in ERBB2-amplified breast carcinomas enhances ErbB-2 oncogenic potency and favors resistance to Herceptin." Oncogene 24, no. 28 (April 25, 2005): 4540–48. http://dx.doi.org/10.1038/sj.onc.1208658.

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Khanam, Kazi Farzana, Tamanna Chowdhury, Sultana Gulshana Banu, and Shahedul Islam. "Determination of HER-2/neu gene Status by Chromogenic in Situ Hybridisation Assay on Borderline (2+) Immunohistochemistry Cases in Patients with Invasive Breast Carcinoma: An Experimental Study on Preserved Tissue." Bangladesh Medical Research Council Bulletin 43, no. 1 (January 2, 2018): 08–15. http://dx.doi.org/10.3329/bmrcb.v43i1.35137.

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HER-2 (also known as HER-2/neu) is a member of the epidermal growth factor (EGF) receptor family. The amplification of oncogene HER-2 is presented in 20 to 30% of breast cancers and results in an increase of the protein expression. HER-2 over expression has also been shown to correlate with poor prognosis. It is associated with poorly differentiated high grade tumors with lymph node involvement, greater risk of recurrence and relative resistance to some types of chemotherapy. The receptor is however a target for treatment with anti HER-2 antibody trastuzumab (Herceptin). Immunohistochemistry analysis for HER 2 scoring is subjective, requires trained personnel and expertise. One of the main concerns with IHC is that there is evidence of significant inter-observer variation in the assessment of staining, which can lead to misclassification of HER2 status. Chromogenic in situ hybridization (CISH) testing is sensitive and specific in detecting HER-2/neu gene amplification. Direct evaluation of gene amplification using CISH assay is a reliable method for routine diagnostic evaluation of HER2/neu status in breast cancer patients, especially in specimens showing 2+ IHC score. This observational experimental study was carried out in the Department of Pathology, Bangabandhu Sheikh Mujib Medical University, Dhaka, during the period of July 2014 to June 2015, The aim of this study was to assess HER-2 expression accurately in equivocal immunohistochemistry (2+) invasive breast cancer cases by Chromogenic in situ hybridization (CISH) and to associate the findings of CISH assay with the histologic prognostic and predictive factors (eg: tumor size, regional lymph node metastases, tumor grade and type. A total of 20 archival paraffin tissue blocks and IHC slides with IHC score 2+ for HER-2 were included in this study. All the slides were reviewed. CISH assay was done on section from archival paraffin block.CISH assay showed amplification of the HER-2 neu gene in 30% of cases. Majority (60%) was nonamplified. In two cases the results were unsatisfactory for interpretation. The differences were not statistically significant (p>0.05) among three groups (amplified, nonamplified and unsatisfactory) regarding the baseline characteristics (age and sex) with CISH. All the results of CISH assay in association with tumor size, tumor grade and lymphnode metastasis were not statistically significant. HER-2 / neu status is the one of the most important prognostic and predictive factor. It is a target for treatment with anti HER-2 antibody trastuzumab (Herceptin). Detection of HER-2/ neu status by IHC may sometimes be difficult and inaccurate, specially in IHC score 2+ cases. Based on the findings of the study, CISH can be considered a useful, simple and reproducible method for detecting HER-2/ neu gene amplification in cases with borderline (2+) immunohistochemistry score , and patients may be benefited from Trastuzumab therapy.

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Fasih, Aisha, Humphrey Fonge, Zhongli Cai, Jeffrey V. Leyton, Ilia Tikhomirov, Susan J. Done, and Raymond M. Reilly. "111In-Bn-DTPA-nimotuzumab with/without modification with nuclear translocation sequence (NLS) peptides: an Auger electron-emitting radioimmunotherapeutic agent for EGFR-positive and trastuzumab (Herceptin)-resistant breast cancer." Breast Cancer Research and Treatment 135, no. 1 (June 27, 2012): 189–200. http://dx.doi.org/10.1007/s10549-012-2137-y.

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Oliveras-Ferraros, Cristina, Alejandro Vazquez-Martin, Begoña Martin-Castillo, Silvia Cufí, Sonia Del Barco, Eugeni Lopez-Bonet, Joan Brunet, and Javier A. Menendez. "Dynamic emergence of the mesenchymal CD44posCD24neg/low phenotype in HER2-gene amplified breast cancer cells with de novo resistance to trastuzumab (Herceptin)." Biochemical and Biophysical Research Communications 397, no. 1 (June 2010): 27–33. http://dx.doi.org/10.1016/j.bbrc.2010.05.041.

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Li, Xi Ru, Yan Jun Zhang, Mei Liu, Yi Qiong Zheng, and Hui Yi Yang. "PIK3CA as a predictor of the clinical efficacy for epirubicin plus docetaxel neoadjuvant chemotherapy in breast cancer." Journal of Clinical Oncology 30, no. 27_suppl (September 20, 2012): 113. http://dx.doi.org/10.1200/jco.2012.30.27_suppl.113.

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113 Background: PIK3CAgene mutations are the most common activating mutations in human breast cancer (BC). Its association with the resistance to herceptin in HER2-positive BC was reported, but whether it’s related to the efficacy of neoadjuvant chemotherapy is unknown. Methods: We reviewed records of 108 patients with BC treated with epirubicin plus docetaxel neoadjuvant chemotherapy between June 2005 and April 2011. 92 patients’ clinical and pathologic objective response data were collected. FFPE tumor biopsies obtained at the time of diagnoses (and before treatment) were collected. EGFR, KRAS, BRAF, PIK3CA mutations and HER2, PTEN, EGFR mRNA expression were analyzed by liquidchip technology. Chi-square test and Fisher’s exact test were used in statistical analysis. A p value less than 0.05 was considered statistically significant. Results: No mutation was detected in EGFR, KRAS and BRAF. The mutation rate of PIK3CA was 35.1% (38/108), and mutation rates of E542K, E545K, H1047L and H1047R were 3.7, 10.2, 3.7 and 17.6% respectively. More PIK3CA mutations were detected in HER2 high expression tumors (p=0.018). No correlation was found between PIK3CA mutations and PTEN, EGFR expression. Clinical response (CR+PR, 63/92) was associated with PIK3CA mutations (p=0.002). However, PIK3CA mutations rate between pathologic complete release (pCR, 7/92) and non-pCR group was not significantly different (p=0.422). Conclusions: PIK3CA mutation may predict better clinical response in BC patients treated with epirubicin plus docetaxel neoadjuvant chemotherapy. More studies are needed to validate these results and the correlation between PIK3CA mutations and pCR.

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Arnold, K., and D. Eckstein. "MEMORANDUM FOR: Science Writers and Editors on the Journal Press List: Insulin-Like Growth Factor Receptors May Be Involved in Development of Resistance to the Breast Cancer Drug Herceptin." JNCI Journal of the National Cancer Institute 93, no. 24 (December 19, 2001): 1829. http://dx.doi.org/10.1093/jnci/93.24.1829-a.

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Stebbing, J., E. Copson, and S. O’Reilly. "Herceptin (trastuzamab) in advanced breast cancer." Cancer Treatment Reviews 26, no. 4 (August 2000): 287–90. http://dx.doi.org/10.1053/ctrv.2000.0182.

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Irwin, Mary E., Laura Nelson, Janice M. Santiago-O'Farrill, Claudia P. Miller, Doris R. Siwak, Gordon B. Mills, Shulin Li, Dennis P. Hughes, and Joya Chandra. "Small Molecule Inhibitors of HER2 Inhibit Proliferative Signaling and Promote Apoptosis in Ph+ ALL." Blood 118, no. 21 (November 18, 2011): 1397. http://dx.doi.org/10.1182/blood.v118.21.1397.1397.

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Abstract Abstract 1397 The ERBB family of receptor tyrosine kinases (EGFR, Her-2, Her-3 and Her-4) are receptor tyrosine kinases that, through mutation or aberrant expression, serve as oncogenes by promoting hallmark behaviors of cancer in many solid tumors. Previous work has suggested that HER2 is expressed in as much as 30% of B-ALL patients, and correlates with chemoresistance. We therefore hypothesized that HER2 signaling in Ph+ ALL may augment growth signaling and promote other malignant behaviors, such as resistance to cell death and independence from growth factors. Western blot and flow cytometric analyses of two human Ph+ ALL cell lines, Z119 and Z181, revealed cell surface expression of HER2, but not other family members. To determine the role of HER2 signaling in Ph+ ALL cell lines, the pan-HER family small molecule kinase inhibitor canertinib was used, and reverse phase protein array (RPPA) was conducted in Z119 and Z181 cell lines. Briefly, lysates from canertinib treated cells were spotted using a GeneTAC™ G3 arrayer onto nitrocellulose-coated FAST® slides. Incubation of the slides was performed with forty-three antibodies directed towards various cell signaling proteins followed by colorimetric detection and results were subsequently validated by western blotting. RPPA analyses revealed that treatment with canertinib effectively diminished HER2 phosphorylation in both cell lines. Additionally, we found decreased phosphorylation of the pro-survival molecules ribosomal protein S6, p70S6kinase, and c-Src, as well as increased expression of the pro-apoptotic molecules BIM and cleaved-PARP in both Ph+ ALL cell lines. Congruent with these findings, elevated activity of the executioner caspase 3 and increased DNA fragmentation, two distinct biochemical markers of apoptosis, were present after canertinib treatment in Z181 and Z119 cells, suggesting that inhibition of HER2 signaling results in programmed cell death of Ph+ ALL cell lines. This induction of apoptosis paralleled a decrease in overall proliferation of these cell lines, further implicating HER2 signaling in proliferation of Ph+ ALL. Next, we analyzed if clinically approved inhibitors of HER2 function could be utilized to produce the same biological consequence as canertinib in Ph+ ALL cell lines. Lapatinib (Tykerb) is a dual EGFR/HER2 small molecule kinase inhibitor approved by the FDA for the treatment of breast cancer. Consistent with our results utilizing canertinib, lapatinib was capable of inhibiting proliferation of both Z119 and Z181 cell lines. Interestingly, the FDA approved monoclonal antibody HER2 inhibitor trastuzumab (Herceptin) did not inhibit proliferation of these cell lines. Similarly, trimerized herceptin conjugates, which improve internalization of HER2 receptor, also had no effect on Ph+ ALL cell line proliferation. These results highlight an important distinction between the effects of the intracellular small molecule inhibitors of HER2 and monoclonal HER2 antibodies. In particular, extracellular engagement of the HER2 receptor by monoclonal antibodies may not be effective in targeting the HER2 signaling pathways required for proliferation and survival of Ph+ ALL. Taken together, our studies suggest that HER2 may play an important role in growth and survival signaling of Ph+ ALL cell lines and inhibition of HER2 with small molecule kinase inhibitors may improve treatment regimens. Thus, additional studies are warranted to determine the importance of HER2 in clinical specimens and the potential benefit of combining HER2 inhibitor therapy with imatinib treatment for Ph+ ALL. Disclosures: Mills: Glaxosmithkline: Research Funding; Pfizer: Research Funding.

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AULT, ALICIA. "Herceptin Approved for Early-Stage Breast Cancer." Family Practice News 37, no. 2 (January 2007): 42. http://dx.doi.org/10.1016/s0300-7073(07)70098-1.

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Ismael, Gustavo, Daniela Dornelles Rosa, Evandro de Azambuja, Sofia Braga, and Martine Piccart-Gebhart. "Trastuzumab (Herceptin) for Early-Stage Breast Cancer." Hematology/Oncology Clinics of North America 21, no. 2 (April 2007): 239–56. http://dx.doi.org/10.1016/j.hoc.2007.03.003.

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Murray, S. "Trastuzumab (Herceptin) and HER2-positive breast cancer." Canadian Medical Association Journal 174, no. 1 (January 3, 2006): 36–37. http://dx.doi.org/10.1503/cmaj.051452.

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Kearney, Nora, and Gaye McPhail. "Herceptin®: implications for breast cancer management." European Journal of Oncology Nursing 4 (March 2000): 37–41. http://dx.doi.org/10.1054/ejon.2000.0074.

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Dean-Colomb, Windy, and Francisco J. Esteva. "Her2-positive breast cancer: Herceptin and beyond." European Journal of Cancer 44, no. 18 (December 2008): 2806–12. http://dx.doi.org/10.1016/j.ejca.2008.09.013.

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McMillan, N. "High hopes for Herceptin in inflammatory breast cancer." Inpharma Weekly &NA;, no. 1609 (October 2007): 13–14. http://dx.doi.org/10.2165/00128413-200716090-00029.

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McNeil, C. "Herceptin Raises Its Sights Beyond Advanced Breast Cancer." JNCI Journal of the National Cancer Institute 90, no. 12 (June 17, 1998): 882–83. http://dx.doi.org/10.1093/jnci/90.12.882.

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BURRISIII, H. "Docetaxel (Taxotere) plus trastuzumab (Herceptin) in breast cancer." Seminars in Oncology 28 (February 2001): 38–44. http://dx.doi.org/10.1016/s0093-7754(01)90191-5.

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Patani, N., and K. Mokbel. "Herceptin and breast cancer: An overview for surgeons." Surgical Oncology 19, no. 1 (March 2010): e11-e21. http://dx.doi.org/10.1016/j.suronc.2008.11.001.

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