The past decade of research into HER2-overexpressing breast cancer has provided significant insight into the mechanisms by which HER2 signaling drives tumor progression, as well as potential mechanisms by which cancer cells escape the anticancer activity of HER2-targeted therapy. Many of these preclinical findings have been translated into clinical development, resulting in novel combinations of HER2-targeted therapies and combinations of trastuzumab plus inhibitors of resistance pathways. In this paper, we will discuss proposed mechanisms of trastuzumab resistance, including epitope masking, cross signaling from other cell surface receptors, hyperactive downstream signaling, and failure to induce antibody-dependent cellular cytotoxicity. In addition, we will discuss the molecular mechanisms of action of dual HER2 inhibition, specifically the combination of trastuzumab plus lapatinib or trastuzumab with pertuzumab. We will also discuss data supporting therapeutic combinations of trastuzumab with agents targeted against molecules implicated in trastuzumab resistance. The roles of insulin-like growth factor-I receptor and the estrogen receptor are discussed in the context of resistance to HER2-targeted therapies. Finally, we will examine the major issues that need to be addressed in order to translate these combinations from the bench to the clinic, including the need to establish relevant biomarkers to select for those patients who are most likely to benefit from a particular drug combination. 1. Introduction The HER2 (erbB2/neu) receptor tyrosine kinase gene is amplified and overexpressed at the protein level in 20–30% of metastatic breast cancers. HER2 overexpression represents an example of oncogene addiction in many of these cancers, as HER2 blockade or kinase inhibition achieves durable responses in many patients with metastatic HER2-overexpressing breast cancer. The first-line treatment for this subtype of breast cancers is the HER2 monoclonal antibody trastuzumab. In combination with cytotoxic chemotherapy, trastuzumab has revolutionized treatment and clinical outcome for patients whose breast tumors express high levels of the HER2 protein. Despite remarkable success, response rates are usually limited in duration, suggesting that the development of resistance is a clinical problem. Research published during the past decade has identified multiple molecular mechanisms contributing to trastuzumab resistance. In addition, recent studies have suggested novel combinations of drugs that will benefit patients who have shown disease progression on prior
References
[1]
L. C. Padhy, C. Shih, D. Cowing, R. Finkelstein, and R. A. Weinberg, “Identification of a phosphoprotein specifically induced by the transforming DNA of rat neuroblastomas,” Cell, vol. 28, no. 4, pp. 865–871, 1982.
[2]
A. L. Schechter, D. F. Stern, and L. Vaidyanathan, “The neu oncogene: an erb-B-related gene encoding a 185,000-M(r) tumour antigen,” Nature, vol. 312, no. 5994, pp. 513–516, 1984.
[3]
C. I. Bargmann, M. C. Hung, and R. A. Weinberg, “The neu oncogene encodes an epidermal growth factor receptor-related protein,” Nature, vol. 319, no. 6050, pp. 226–230, 1986.
[4]
L. Coussens, T. L. Yang-Feng, and Y. C. Liao, “Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene,” Science, vol. 230, no. 4730, pp. 1132–1139, 1985.
[5]
C. I. Bargmann, M. C. Hung, and R. A. Weinberg, “Multiple independent activations of the neu oncogene by a point mutation altering the transmembrane domain of p185,” Cell, vol. 45, no. 5, pp. 649–657, 1986.
[6]
R. Brandt, A. M. L. Wong, and N. E. Hynes, “Mammary glands reconstituted with Neu/ErbB2 transformed HC11 cells provide a novel orthotopic tumor model for testing anti-cancer agents,” Oncogene, vol. 20, no. 39, pp. 5459–5465, 2001.
[7]
D. B. Weiner, J. Liu, J. A. Cohen, W. V. Williams, and M. I. Greene, “A point mutation in the neu oncogene mimics ligand induction of receptor aggregation,” Nature, vol. 339, no. 6221, pp. 230–231, 1989.
[8]
D. J. Slamon, G. M. Clark, S. G. Wong, W. J. Levin, A. Ullrich, and W. L. McGuire, “Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene,” Science, vol. 235, no. 4785, pp. 177–182, 1987.
[9]
A. L. Schechter, M. C. Hung, and L. Vaidyanathan, “The neu gene: an erbB-homologous gene distinct from and unlinked to the gene encoding the EGF receptor,” Science, vol. 229, no. 4717, pp. 976–978, 1985.
[10]
R. M. Hudziak, J. Schlessinger, and A. Ullrich, “Increased expression of the putative growth factor receptor p185HER2 causes transformation and tumorigenesis of NIH 3T3 cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 84, no. 20, pp. 7159–7163, 1987.
[11]
M. E. Arcila, J. E. Chaft, K. Nafa, S. Roy-Chowdhuri, C. Lau, M. Zaidinski, et al., “Prevalence, clinicopathologic associations, and molecular spectrum of ERBB2 (HER2) tyrosine kinasemutations in lung adenocarcinomas,” Clinical Cancer Research, vol. 18, no. 18, pp. 4910–4918, 2012.
[12]
B. L. Margolis, I. Lax, R. Kris et al., “All autophosphorylation sites of epidermal growth factor (EGF) receptor and HER2/neu are located in their carboxyl-terminal tails. Identification of a novel site in EGF receptor,” Journal of Biological Chemistry, vol. 264, no. 18, pp. 10667–10671, 1989.
[13]
R. Hazan, B. Margolis, M. Dombalagian, A. Ullrich, A. Zilberstein, and J. Schlessinger, “Identification of autophosphorylation sites of HER2/neu,” Cell Growth & Differentiation, vol. 1, no. 1, pp. 3–7, 1990.
[14]
D. Graus-Porta, R. R. Beerli, J. M. Daly, and N. E. Hynes, “ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling,” EMBO Journal, vol. 16, no. 7, pp. 1647–1655, 1997.
[15]
E. Penuel, R. W. Akita, and M. X. Sliwkowski, “Identification of a region within the ErbB2/HER2 intracellular domain that is necessary for ligand-independent association,” Journal of Biological Chemistry, vol. 277, no. 32, pp. 28468–28473, 2002.
[16]
X. Qian, W. C. Dougall, M. E. Hellman, and M. I. Greene, “Kinase-deficient neu proteins suppress epidermal growth factor receptor function and abolish cell transformation,” Oncogene, vol. 9, no. 5, pp. 1507–1514, 1994.
[17]
X. Qian, C. M. LeVea, J. K. Freeman, W. C. Dougall, and M. I. Greene, “Heterodimerization of epidermal growth factor receptor and wild-type or kinase-deficient Neu: a mechanism of interreceptor kinase activation and transphosphorylation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 4, pp. 1500–1504, 1994.
[18]
X. Qian, D. M. O'Rourke, H. Zhao, and M. I. Greene, “Inhibition of p185(neu) kinase activity and cellular transformation by co-expression of a truncated neu protein,” Oncogene, vol. 13, no. 10, pp. 2149–2157, 1996.
[19]
T. Kumagai, J. G. Davis, T. Horie, D. M. O'Rourke, and M. I. Greene, “The role of distinct p185neu extracellular subdomains for dimerization with the epidermal growth factor (EGF) receptor and EGF-mediated signaling,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 10, pp. 5526–5531, 2001.
[20]
P. J. Brennan, T. Kumogai, A. Berezov, R. Murali, and M. I. Greene, “HER2/neu: mechanisms of dimerization/oligomerization,” Oncogene, vol. 19, no. 53, pp. 6093–6101, 2000.
[21]
P. P. Di Fiore, J. H. Pierce, M. H. Kraus, et al., “erbB-2 is a potent oncogene when overexpressed in NIH/3T3 cells,” Science, vol. 237, no. 4811, pp. 178–182, 1987.
[22]
E. Di Marco, J. H. Pierce, C. L. Knicley, and P. P. Di Fiore, “Transformation of NIH 3T3 cells by overexpression of the normal coding sequence of the rat neu gene,” Molecular and Cellular Biology, vol. 10, no. 6, pp. 3247–3252, 1990.
[23]
A. Samanta, C. M. LeVea, W. C. Dougall, X. Qian, and M. I. Greene, “Ligand and p185(c-neu) density govern receptor interactions and tyrosine kinase activation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 5, pp. 1711–1715, 1994.
[24]
R. Ghosh, A. Narasanna, S. E. Wang et al., “Trastuzumab has preferential activity against breast cancers driven by HER2 homodimers,” Cancer Research, vol. 71, no. 5, pp. 1871–1882, 2011.
[25]
Q. B. She, S. Chandarlapaty, Q. Ye et al., “Breast tumor cells with P13K mutation or HER2 amplification are selectively addicted to Akt signaling,” PLoS ONE, vol. 3, no. 8, article e3065, 2008.
[26]
E. Yao, W. Zhou, S. T. Lee-Hoeflich et al., “Suppression of HER2/HER3-mediated growth of breast cancer cells with combinations of GDC-0941 PI3K inhibitor, trastuzumab, and pertuzumab,” Clinical Cancer Research, vol. 15, no. 12, pp. 4147–4156, 2009.
[27]
T. Utermark, T. Rao, H. Cheng, Q. Wang, S. H. Lee, Z. C. Wang, et al., “The p110alpha and p110beta isoforms of PI3K play divergent roles in mammary gland development and tumorigenesis,” Genes & Development, vol. 26, pp. 1573–1586, 2012.
[28]
H. Kurokawa, A. E. G. Lenferink, J. F. Simpson et al., “Inhibition of HER2/neu (erbB-2) and mitogen-activated protein kinases enhances tamoxifen action against HER2-overexpressing, tamoxifen-resistant breast cancer cells,” Cancer Research, vol. 60, no. 20, pp. 5887–5894, 2000.
[29]
P. J. Roberts, J. E. Usary, D. B. Darr, P. M. Dillon, A. D. Pfefferle, M. C. Whittle, et al., “Combined PI3K/mTOR and MEK inhibition provides broad antitumor activity in faithful murine cancer models,” Clinical Cancer Research, vol. 18, no. 19, pp. 5290–5303, 2012.
[30]
S. Mabuchi, C. Kawase, D. A. Altomare et al., “mTOR is a promising therapeutic target both in cisplatin-sensitive and cisplatin-resistant clear cell carcinoma of the ovary,” Clinical Cancer Research, vol. 15, no. 17, pp. 5404–5413, 2009.
[31]
R. M. Hudziak, G. D. Lewis, M. Winget, B. M. Fendly, H. M. Shepard, and A. Ullrich, “p185(HER2) monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor,” Molecular and Cellular Biology, vol. 9, no. 3, pp. 1165–1172, 1989.
[32]
R. Kumar, H. M. Shepard, and J. Mendelsohn, “Regulation of phosphorylation of the c-erbB-2/HER2 gene product by a monoclonal antibody and serum growth factor(s) in human mammary carcinoma cells,” Molecular and Cellular Biology, vol. 11, no. 2, pp. 979–986, 1991.
[33]
R. J. Pietras, B. M. Fendly, V. R. Chazin, M. D. Pegram, S. B. Howell, and D. J. Slamon, “Antibody to HER-2/neu receptor blocks DNA repair after cisplatin in human breast and ovarian cancer cells,” Oncogene, vol. 9, no. 7, pp. 1829–1838, 1994.
[34]
R. J. Pietras, M. D. Pegram, R. S. Finn, D. A. Maneval, and D. J. Slamon, “Remission of human breast cancer xenografts on therapy with humanized monoclonal antibody to HER-2 receptor and DNA-reactive drugs,” Oncogene, vol. 17, no. 17, pp. 2235–2249, 1998.
[35]
P. Carter, L. Presta, C. M. Gorman et al., “Humanization of an anti-p185(HER2) antibody for human cancer therapy,” Proceedings of the National Academy of Sciences of the United States of America, vol. 89, no. 10, pp. 4285–4289, 1992.
[36]
J. Baselga, L. Norton, J. Albanell, Y. M. Kim, and J. Mendelsohn, “Recombinant humanized anti-HER2 antibody (herceptin(TM)) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts,” Cancer Research, vol. 58, no. 13, pp. 2825–2831, 1998.
[37]
M. D. Pegram and D. J. Slamon, “Combination therapy with trastuzumab (Herceptin) and cisplatin for chemoresistant metastatic breast cancer: evidence for receptor-enhanced chemosensitivity,” Seminars in Oncology, vol. 26, no. 4, pp. 89–95, 1999.
[38]
M. X. Sliwkowski, J. A. Lofgren, G. D. Lewis, T. E. Hotaling, B. M. Fendly, and J. A. Fox, “Nonclinical studies addressing the mechanism of action of trastuzumab (Herceptin),” Seminars in Oncology, vol. 26, no. 4, pp. 60–70, 1999.
[39]
R. Nahta, “Pharmacological strategies to overcome HER2 cross-talk and trastuzumab resistance,” Current Medicinal Chemistry, vol. 19, no. 7, pp. 1065–1075, 2012.
[40]
R. Nahta and F. J. Esteva, “HER2 therapy: molecular mechanisms of trastuzumab resistance,” Breast Cancer Research, vol. 8, no. 6, article no. 215, 2006.
[41]
R. Nahta and F. J. Esteva, “Herceptin: mechanisms of action and resistance,” Cancer Letters, vol. 232, no. 2, pp. 123–138, 2006.
[42]
R. Nahta and F. J. Esteva, “Trastuzumab: triumphs and tribulations,” Oncogene, vol. 26, no. 25, pp. 3637–3643, 2007.
[43]
R. Nahta, S. Shabaya, T. Ozbay, and D. L. Rowe, “Personalizing HER2-targeted therapy in metastatic breast cancer beyond HER2 status: what we have learned from clinical specimens,” Current Pharmacogenomics and Personalized Medicine, vol. 7, no. 4, pp. 263–274, 2009.
[44]
R. Nahta, D. Yu, M. C. Hung, G. N. Hortobagyi, and F. J. Esteva, “Mechanisms of disease: understanding resistance to HER2-targeted therapy in human breast cancer,” Nature Clinical Practice Oncology, vol. 3, no. 5, pp. 269–280, 2006.
[45]
M. Cuello, S. A. Ettenberg, A. S. Clark et al., “Down-regulation of the erbB-2 receptor by trastuzumab (Herceptin) enhances tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in breast and ovarian cancer cell lines that overexpress erbB-2,” Cancer Research, vol. 61, no. 12, pp. 4892–4900, 2001.
[46]
D. Gajria and S. Chandarlapaty, “HER2-amplified breast cancer: mechanisms of trastuzumab resistance and novel targeted therapies,” Expert Review of Anticancer Therapy, vol. 11, no. 2, pp. 263–275, 2011.
[47]
M. A. Molina, J. Codony-Servat, J. Albanell, F. Rojo, J. Arribas, and J. Baselga, “Trastuzumab (Herceptin), a humanized anti-HER2 receptor monoclonal antibody, inhibits basal and activated HER2 ectodomain cleavage in breast cancer cells,” Cancer Research, vol. 61, no. 12, pp. 4744–4749, 2001.
[48]
T. T. Junttila, R. W. Akita, K. Parsons et al., “Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941,” Cancer Cell, vol. 15, no. 5, pp. 429–440, 2009.
[49]
H. A. Lane, A. B. Motoyama, I. Beuvink, and N. E. Hynes, “Modulation of p27/Cdk2 complex formation through 4D5-mediated inhibition of HER2 receptor signaling,” Annals of Oncology, vol. 12, Supplement 1, pp. S21–S22, 2001.
[50]
X. F. Le, F. X. Claret, A. Lammayot et al., “The role of cyclin-dependent kinase inhibitor p27Kip1 in anti-HER2 antibody-induced G1 cell cycle arrest and tumor growth inhibition,” Journal of Biological Chemistry, vol. 278, no. 26, pp. 23441–23450, 2003.
[51]
Y. Izumi, L. Xu, E. Di Tomaso, D. Fukumura, and R. K. Jain, “Herceptin acts as an anti-angiogenic cocktail,” Nature, vol. 416, no. 6878, pp. 279–280, 2002.
[52]
L. Arnould, M. Gelly, F. Penault-Llorca et al., “Trastuzumab-based treatment of HER2-positive breast cancer: an antibody-dependent cellular cytotoxicity mechanism?” British Journal of Cancer, vol. 94, no. 2, pp. 259–267, 2006.
[53]
R. A. Clynes, T. L. Towers, L. G. Presta, and J. V. Ravetch, “Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets,” Nature Medicine, vol. 6, no. 4, pp. 443–446, 2000.
[54]
A. U. Buzdar, N. K. Ibrahim, D. Francis et al., “Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer,” Journal of Clinical Oncology, vol. 23, no. 16, pp. 3676–3685, 2005.
[55]
E. A. Perez, E. H. Romond, V. J. Suman, J. H. Jeong, N. E. Davidson, C. E. Geyer Jr., et al., “Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31,” Journal of Clinical Oncology, vol. 29, pp. 3366–3373, 2011.
[56]
J. Baselga, D. Tripathy, J. Mendelsohn et al., “Phase II Study of Weekly Intravenous Recombinant Humanized Anti-p185HER2 Monoclonal Antibody in Patients with HER2/neu-Overexpressing Metastatic Breast Cancer,” Journal of Clinical Oncology, vol. 14, no. 3, pp. 737–744, 1996.
[57]
M. A. Cobleigh, C. L. Vogel, D. Tripathy et al., “Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease,” Journal of Clinical Oncology, vol. 17, no. 9, pp. 2639–2648, 1999.
[58]
C. L. Vogel, M. A. Cobleigh, D. Tripathy et al., “Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer,” Journal of Clinical Oncology, vol. 20, no. 3, pp. 719–726, 2002.
[59]
F. J. Esteva, V. Valero, D. Booser et al., “Phase II study of weekly docetaxel and trastuzumab for patients with HER-2-overexpressing metastatic breast cancer,” Journal of Clinical Oncology, vol. 20, no. 7, pp. 1800–1808, 2002.
[60]
A. D. Seidman, M. N. Fornier, F. J. Esteva et al., “Weekly trastuzumab and paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and gene amplification,” Journal of Clinical Oncology, vol. 19, no. 10, pp. 2587–2595, 2001.
[61]
D. J. Slamon, B. Leyland-Jones, S. Shak et al., “Use of chemotherapy plus a monoclonal antibody against her2 for metastatic breast cancer that overexpresses HER2,” The New England Journal of Medicine, vol. 344, no. 11, pp. 783–792, 2001.
[62]
C. L. Arteaga, M. X. Sliwkowski, C. K. Osborne, E. A. Perez, F. Puglisi, and L. Gianni, “Treatment of HER2-positive breast cancer: current status and future perspectives,” Nature Reviews Clinical Oncology, vol. 9, pp. 16–32, 2012.
[63]
T. A. Bailey, H. Luan, R. J. Clubb, M. Naramura, V. Band, S. M. Raja, et al., “Mechanisms of Trastuzumab resistance in ErbB2-driven breast cancer and newer opportunities to overcome therapy resistance,” Journal of Carcinogenesis, vol. 10, article 28, 2011.
[64]
R. Nahta, T. Takahashi, N. T. Ueno, M. C. Hung, and F. J. Esteva, “P27kip1 down-regulation is associated with trastuzumab resistance in breast cancer cells,” Cancer Research, vol. 64, no. 11, pp. 3981–3986, 2004.
[65]
M. Komatsu, C. A. C. Carraway, N. L. Fregien, and K. L. Carraway, “Reversible disruption of cell-matrix and cell-cell interactions by overexpression of sialomucin complex,” Journal of Biological Chemistry, vol. 272, no. 52, pp. 33245–33254, 1997.
[66]
K. L. Carraway III, E. A. Rossi, M. Komatsu et al., “An intramembrane modulator of the ErbB2 receptor tyrosine kinase that potentiates neuregulin signaling,” Journal of Biological Chemistry, vol. 274, no. 9, pp. 5263–5266, 1999.
[67]
S. A. Price-Schiavi, S. Jepson, P. Li et al., “Rat MUC4 (sialomucin complex) reduces binding of anti-ErbB2 antibodies to tumor cell surfaces, a potential mechanism for herceptin resistance,” International Journal of Cancer, vol. 99, no. 6, pp. 783–791, 2002.
[68]
K. Wu, P. J. I. Salas, L. Yee, N. Fregien, and K. L. Carraway, “Tissue and tumor expression of a cell surface glycoprotein complex containing an integral membrane glycoprotein activator of p185(neu),” Oncogene, vol. 9, no. 11, pp. 3139–3147, 1994.
[69]
P. Nagy, E. Friedl？nder, M. Tanner et al., “Decreased accessibility and lack of activation of ErbB2 in JIMT-1, a herceptin-resistant, MUC4-expressing cancer cell line,” Cancer Research, vol. 65, no. 2, pp. 473–482, 2005.
[70]
A. C. Chen, I. Migliaccio, M. Rimawi, S. Lopez-Tarruella, C. J. Creighton, S. Massarweh, et al., “Upregulation of mucin4 in ER-positive/HER2-overexpressing breast cancer xenografts with acquired resistance to endocrine and HER2-targeted therapies,” Breast Cancer Research and Treatment, vol. 134, pp. 583–593, 2012.
[71]
W. Xia, L. H. Liu, P. Ho, and N. L. Spector, “Truncated ErbB2 receptor (p95ErbB2) is regulated by heregulin through heterodimer formation with ErbB3 yet remains sensitive to the dual EGFR/ErbB2 kinase inhibitor GW572016,” Oncogene, vol. 23, no. 3, pp. 646–653, 2004.
[72]
M. Scaltriti, F. Rojo, A. Oca？a et al., “Expression of p95HER2, a truncated form of the HER2 receptor, and response to Anti-HER2 therapies in breast cancer,” Journal of the National Cancer Institute, vol. 99, no. 8, pp. 628–638, 2007.
[73]
M. Scaltriti, S. Chandarlapaty, L. Prudkin et al., “Clinical benefit of lapatinib-based therapy in patients with human epidermal growth factor receptor 2-positive breast tumors coexpressing the truncated p95HER2 receptor,” Clinical Cancer Research, vol. 16, no. 9, pp. 2688–2695, 2010.
[74]
J. Sperinde, X. Jin, J. Banerjee et al., “Quantitation of p95HER2 in paraffin sections by using a p95-specific antibody and correlation with outcome in a cohort of trastuzumab-treated breast cancer patients,” Clinical Cancer Research, vol. 16, no. 16, pp. 4226–4235, 2010.
[75]
A. Vazquez-Martin, C. Oliveras-Ferraros, S. Cufí, S. Del Barco, B. Martin-Castillo, and J. A. Menendez, “Lapatinib, a dual HER1/HER2 tyrosine kinase inhibitor, augments basal cleavage of HER2 extracellular domain (ECD) to inhibit HER2-driven cancer cell growth,” Journal of Cellular Physiology, vol. 226, no. 1, pp. 52–57, 2011.
[76]
J. Anido, M. Scaltriti, J. J. B. Serra et al., “Biosynthesis of tumorigenic HER2 C-terminal fragments by alternative initiation of translation,” EMBO Journal, vol. 25, no. 13, pp. 3234–3244, 2006.
[77]
S. M. Pupa, S. Menard, D. Morelli, B. Pozzi, G. De Palo, and M. I. Colnaghi, “The extracellular domain of the c-erbB-2 oncoprotein is released from tumor cells by proteolytic cleavage,” Oncogene, vol. 8, no. 11, pp. 2917–2923, 1993.
[78]
R. Zagozdzon, W. M. Gallagher, and J. Crown, “Truncated HER2: implications for HER2-targeted therapeutics,” Drug Discovery Today, vol. 16, pp. 810–816, 2011.
[79]
T. M. Ward, E. Iorns, X. Liu, N. Hoe, P. Kim, S. Singh, et al., “Truncated p110 ERBB2 induces mammary epithelial cell migration, invasion and orthotopic xenograft formation, and is associated with loss of phosphorylated STAT5,” Oncogene. In press.
[80]
K. Pedersen, P. D. Angelini, S. Laos et al., “A naturally occurring HER2 carboxy-terminal fragment promotes mammary tumor growth and metastasis,” Molecular and Cellular Biology, vol. 29, no. 12, pp. 3319–3331, 2009.
[81]
R. Nahta, “Deciphering the role of insulin-like growth factor-I receptor in trastuzumab resistance,” Chemotherapy Research and Practice, vol. 2012, Article ID 648965, 7 pages, 2012.
[82]
Y. Lu, X. Zi, Y. Zhao, D. Mascarenhas, and M. Pollak, “Insulin-like growth factor-I receptor signaling and resistance to transtuzumab (Herceptin),” Journal of the National Cancer Institute, vol. 93, no. 24, pp. 1852–1857, 2001.
[83]
L. Jerome, N. Alami, S. Belanger et al., “Recombinant human insulin-like growth factor binding protein 3 inhibits growth of human epidermal growth factor receptor-2-overexpressing breast tumors and potentiates herceptin activity in vivo,” Cancer Research, vol. 66, no. 14, pp. 7245–7252, 2006.
[84]
A. K. Chakraborty, K. Liang, and M. P. DiGiovanna, “Co-targeting insulin-like growth factor I receptor and HER2: dramatic effects of HER2 inhibitors on nonoverexpressing breast cancer,” Cancer Research, vol. 68, no. 5, pp. 1538–1545, 2008.
[85]
X. Huang, L. Gao, S. Wang et al., “Heterotrimerization of the growth factor receptors erbB2, erbB3, and insulin-like growth factor-I receptor in breast cancer cells resistant to herceptin,” Cancer Research, vol. 70, no. 3, pp. 1204–1214, 2010.
[86]
R. Nahta, L. X. Yuan, B. Zhang, R. Kobayashi, and F. J. Esteva, “Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells,” Cancer Research, vol. 65, pp. 11118–11128, 2005.
[87]
D. L. Rowe, T. Ozbay, L. M. Bender, and R. Nahta, “Nordihydroguaiaretic acid, a cytotoxic insulin-like growth factor-I receptor/HER2 inhibitor in trastuzumab-resistant breast cancer,” Molecular Cancer Therapeutics, vol. 7, no. 7, pp. 1900–1908, 2008.
[88]
K. Lindemann, J. Resau, J. N？hrig et al., “Differential expression of c-Met, its ligand HGF/SF and HER2/neu in DCIS and adjacent normal breast tissue,” Histopathology, vol. 51, no. 1, pp. 54–62, 2007.
[89]
H. Khoury, M. A. Naujokas, D. Zuo et al., “HGF converts ErbB2/Neu epithelial morphogenesis to cell invasion,” Molecular Biology of the Cell, vol. 16, no. 2, pp. 550–561, 2005.
[90]
D. L. Shattuck, J. K. Miller, K. L. Carraway III, and C. Sweeney, “Met receptor contributes to trastuzumab resistance of Her2-overexpressing breast cancer cells,” Cancer Research, vol. 68, no. 5, pp. 1471–1477, 2008.
[91]
G. Minuti, F. Cappuzzo, R. Duchnowska, J. Jassem, A. Fabi, T. O'Brien, et al., “Increased MET and HGF gene copy numbers are associated with trastuzumab failure in HER2-positive metastatic breast cancer,” British Journal of Cancer, vol. 107, pp. 793–799, 2012.
[92]
J. P. Joshi, N. E. Brown, S. E. Griner, and R. Nahta, “Growth differentiation factor 15 (GDF15)-mediated HER2 phosphorylation reduces trastuzumab sensitivity of HER2-overexpressing breast cancer cells,” Biochemical Pharmacology, vol. 82, pp. 1090–1099, 2011.
[93]
M. R. Bootcov, A. R. Bauskin, S. M. Valenzuela et al., “MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-β superfamily,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 21, pp. 11514–11519, 1997.
[94]
A. J. Bock, H. T. Stavnes, T. Kempf et al., “Expression and clinical role of growth differentiation factor-15 in ovarian carcinoma effusions,” International Journal of Gynecological Cancer, vol. 20, no. 9, pp. 1448–1455, 2010.
[95]
J. Koopmann, C. N. W. Rosenzweig, Z. Zhang et al., “Serum markers in patients with resectable pancreatic adenocarcinoma: macrophage inhibitory cytokine 1 versus CA19-9,” Clinical Cancer Research, vol. 12, no. 2, pp. 442–446, 2006.
[96]
K. S. Selander, D. A. Brown, G. B. Sequeiros et al., “Serum macrophage inhibitory cytokine-1 concentrations correlate with the presence of prostate cancer bone metastases,” Cancer Epidemiology Biomarkers and Prevention, vol. 16, no. 3, pp. 532–537, 2007.
[97]
A. C. Staff, A. J. Bock, C. Becker, T. Kempf, K. C. Wollert, and B. Davidson, “Growth differentiation factor-15 as a prognostic biomarker in ovarian cancer,” Gynecologic Oncology, vol. 118, no. 3, pp. 237–243, 2010.
[98]
J. B. Welsh, L. M. Sapinoso, S. G. Kern et al., “Large-scale delineation of secreted protein biomarkers overexpressed in cancer tissue and serum,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 6, pp. 3410–3415, 2003.
[99]
K. K. Kim, J. J. Lee, Y. Yang, K. H. You, and J. H. Lee, “Macrophage inhibitory cytokine-1 activates AKT and ERK-1/2 via the transactivation of ErbB2 in human breast and gastric cancer cells,” Carcinogenesis, vol. 29, no. 4, pp. 704–712, 2008.
[100]
Y. J. Park, H. Lee, and J. H. Lee, “Macrophage inhibitory cytokine-1 transactivates ErbB family receptors via the activation of Src in SK-BR-3 human breast cancer cells,” BMB Reports, vol. 43, no. 2, pp. 91–96, 2010.
[101]
A. Gallardo, E. Lerma, D. Escuin, A. Tibau, J. Munoz, B. Ojeda, et al., “Increased signalling of EGFR and IGF1R, and deregulation of PTEN/PI3K/Akt pathway are related with trastuzumab resistance in HER2 breast carcinomas,” British Journal of Cancer, vol. 106, no. 8, pp. 1367–1373, 2012.
[102]
K. Berns, H. M. Horlings, B. T. Hennessy et al., “A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer,” Cancer Cell, vol. 12, no. 4, pp. 395–402, 2007.
[103]
Y. Nagata, K. H. Lan, X. Zhou et al., “PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients,” Cancer Cell, vol. 6, no. 2, pp. 117–127, 2004.
[104]
A. C. Faber, K. K. Wong, and J. A. Engelman, “Differences underlying EGFR and HER2 oncogene addiction,” Cell Cycle, vol. 9, no. 5, pp. 851–852, 2010.
[105]
V. Serra, B. Markman, M. Scaltriti et al., “NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations,” Cancer Research, vol. 68, no. 19, pp. 8022–8030, 2008.
[106]
A. C. Faber, D. Li, Y. Song et al., “Differential induction of apoptosis in HER2 and EGFR addicted cancers following PI3K inhibition,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 46, pp. 19503–19508, 2009.
[107]
J. Tanizaki, I. Okamoto, S. Fumita, W. Okamoto, K. Nishio, and K. Nakagawa, “Roles of BIM induction and survivin downregulation in lapatinib-induced apoptosis in breast cancer cells with HER2 amplification,” Oncogene, vol. 30, pp. 4097–4106, 2011.
[108]
R. Gennari, S. Menard, F. Fagnoni et al., “Pilot study of the mechanism of action of preoperative trastuzumab in patients with primary operable breast tumors overexpressing HER2,” Clinical Cancer Research, vol. 10, no. 17, pp. 5650–5655, 2004.
[109]
S. Varchetta, N. Gibelli, B. Oliviero et al., “Elements related to heterogeneity of antibody-dependent cell cytotoxicity in patients under trastuzumab therapy for primary operable breast cancer overexpressing Her2,” Cancer Research, vol. 67, no. 24, pp. 11991–11999, 2007.
[110]
W. E. Carson, R. Parihar, M. J. Lindemann, N. Personeni, J. Dierksheide, N. J. Meropol, et al., “Interleukin-2 enhances the natural killer cell response to Herceptin-coated Her2/neu-positive breast cancer cells,” European Journal of Immunology, vol. 31, pp. 3016–3025, 2001.
[111]
K. Kono, A. Takahashi, F. Ichihara, H. Sugai, H. Fujii, and Y. Matsumoto, “Impaired antibody-dependent cellular cytotoxicity mediated by Herceptin in patients with gastric cancer,” Cancer Research, vol. 62, no. 20, pp. 5813–5817, 2002.
[112]
T. Repka, E. G. Chiorean, J. Gay et al., “Trastuzumab and interleukin-2 in HER2-positive metastatic breast cancer: a pilot study,” Clinical Cancer Research, vol. 9, no. 7, pp. 2440–2446, 2003.
[113]
R. Parihar, P. Nadella, A. Lewis et al., “A phase I study of interleukin 12 with trastuzumab in patients with human epidermal growth factor receptor-2-overexpressing malignancies: analysis of sustained interferon γ production in a subset of patients,” Clinical Cancer Research, vol. 10, no. 15, pp. 5027–5037, 2004.
[114]
H. E. Kohrt, R. Houot, K. Weiskopf, M. J. Goldstein, F. Scheeren, D. Czerwinski, et al., “Stimulation of natural killer cells with a CD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer,” Journal of Clinical Investigation, vol. 122, pp. 1066–1075, 2012.
[115]
C. I. Spiridon, M. A. Ghetie, J. Uhr et al., “Targeting multiple Her-2 epitopes with monoclonal antibodies results in improved antigrowth activity of a human breast cancer cell line in vitro and in vivo,” Clinical Cancer Research, vol. 8, no. 6, pp. 1720–1730, 2002.
[116]
D. W. Rusnak, K. Lackey, K. Affleck et al., “The effects of the novel, reversible epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor, GW2016, on the growth of human normal and tumor-derived cell lines in vitro and in vivo,” Molecular Cancer Therapeutics, vol. 1, no. 2, pp. 85–94, 2001.
[117]
W. Xia, R. J. Mullin, B. R. Keith et al., “Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways,” Oncogene, vol. 21, no. 41, pp. 6255–6263, 2002.
[118]
D. Zhang, A. Pal, W. G. Bornmann et al., “Activity of lapatinib is independent of EGFR expression level in HER2-overexpressing breast cancer cells,” Molecular Cancer Therapeutics, vol. 7, no. 7, pp. 1846–1850, 2008.
[119]
C. E. Geyer, J. Forster, D. Lindquist et al., “Lapatinib plus capecitabine for HER2-positive advanced breast cancer,” The New England Journal of Medicine, vol. 355, no. 26, pp. 2733–2743, 2006.
[120]
K. L. Blackwell, H. J. Burstein, A. M. Storniolo et al., “Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer,” Journal of Clinical Oncology, vol. 28, no. 7, pp. 1124–1130, 2010.
[121]
M. Toi, H. Iwata, Y. Fujiwara et al., “Lapatinib monotherapy in patients with relapsed, advanced, or metastatic breast cancer: efficacy, safety, and biomarker results from Japanese patients phase II studies,” British Journal of Cancer, vol. 101, no. 10, pp. 1676–1682, 2009.
[122]
S. S. Gayle, S. L. Arnold, R. M. O'Regan RM, and R. Nahta, “Pharmacologic inhibition of mTOR improves lapatinib sensitivity in HER2-overexpressing breast cancer cells with primary trastuzumab resistance,” Anti-Cancer Agents in Medicinal Chemistry, vol. 12, pp. 151–162, 2012.
[123]
P. S. Hegde, D. Rusnak, M. Bertiaux et al., “Delineation of molecular mechanisms of sensitivity to lapatinib in breast cancer cell lines using global gene expression profiles,” Molecular Cancer Therapeutics, vol. 6, no. 5, pp. 1629–1640, 2007.
[124]
W. Xia, S. Bacus, P. Hegde et al., “A model of acquired autoresistance to a potent ErbB2 tyrosine kinase inhibitor and a therapeutic strategy to prevent its onset in breast cancer,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 20, pp. 7795–7800, 2006.
[125]
Y. C. Wang, G. Morrison, R. Gillihan, J. Guo, R. M. Ward, X. Fu, et al., “Different mechanisms for resistance to trastuzumab versus lapatinib in HER2-positive breast cancers–role of estrogen receptor and HER2 reactivation,” Breast Cancer Research, vol. 13, article R121, 2011.
[126]
A. Crawford and R. Nahta, “Targeting Bcl-2 in herceptin-resistant breast cancer cell lines,” Current Pharmacogenomics and Personalized Medicine, vol. 9, pp. 184–190, 2011.
[127]
E. E. W. Cohen, M. W. Lingen, L. E. Martin et al., “Response of some head and neck cancers to epidermal growth factor receptor tyrosine kinase inhibitors may be linked to mutation of ERBB2 rather than EGFR,” Clinical Cancer Research, vol. 11, no. 22, pp. 8105–8108, 2005.
[128]
J. W. Lee, Y. H. Soung, S. H. Seo et al., “Somatic mutations of ERBB2 kinase domain in gastric, colorectal, and breast carcinomas,” Clinical Cancer Research, vol. 12, no. 1, pp. 57–61, 2006.
[129]
P. Stephens, C. Hunter, G. Bignell, S. Edkins, H. Davies, J. Teague, et al., “Lung cancer: intragenic ERBB2 kinase mutations in tumours,” Nature, vol. 431, pp. 525–526, 2004.
[130]
R. K. Kancha, N. von Bubnoff, N. Bartosch, C. Peschel, R. A. Engh, and J. Duyster, “Differential sensitivity of ERBB2 kinase domain mutations towards lapatinib,” PLoS One, vol. 6, article e26760, 2011.
[131]
G. E. Konecny, M. D. Pegram, N. Venkatesan et al., “Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells,” Cancer Research, vol. 66, no. 3, pp. 1630–1639, 2006.
[132]
K. L. Blackwell, H. J. Burstein, A. M. Storniolo, H. S. Rugo, G. Sledge, G. Aktan, et al., “Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the egf104900 study,” Journal of Clinical Oncology, vol. 30, pp. 2585–2592, 2012.
[133]
A. Valachis, A. Nearchou, P. Lind, and D. Mauri, “Lapatinib, trastuzumab or the combination added to preoperative chemotherapy for breast cancer: a meta-analysis of randomized evidence,” Breast Cancer Research, vol. 135, no. 3, pp. 655–662, 2012.
[134]
M. Untch, S. Loibl, J. Bischoff, H. Eidtmann, M. Kaufmann, J. U. Blohmer, et al., “Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial,” The Lancet Oncology, vol. 13, pp. 135–144, 2012.
[135]
J. Baselga, I. Bradbury, H. Eidtmann, S. Di Cosimo, E. de Azambuja, C. Aura, et al., “Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial,” The Lancet, vol. 379, pp. 633–640, 2012.
[136]
V. Guarneri, A. Frassoldati, A. Bottini, K. Cagossi, G. Bisagni, S. Sarti, et al., “Preoperative chemotherapy plus trastuzumab, lapatinib, or both in human epidermal growth factor receptor 2-positive operable breast cancer: results of the randomized phase II CHER-LOB stud,” Journal of Clinical Oncology, vol. 30, pp. 1989–1995, 2012.
[137]
R. Nahta, L. X. H. Yuan, Y. Du, and F. J. Esteva, “Lapatinib induces apoptosis in trastuzumab-resistant breast cancer cells: effects on insulin-like growth factor I signaling,” Molecular Cancer Therapeutics, vol. 6, no. 2, pp. 667–674, 2007.
[138]
N. A. O'Brien, B. C. Browne, L. Chow et al., “Activated phosphoinositide 3-kinase/AKT signaling confers resistance to trastuzumab but not lapatinib,” Molecular Cancer Therapeutics, vol. 9, no. 6, pp. 1489–1502, 2010.
[139]
T. Holbro, R. R. Beerli, F. Maurer, M. Koziczak, C. F. Barbas III, and N. E. Hynes, “The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 15, pp. 8933–8938, 2003.
[140]
H. H. Kim, S. L. Sierke, and J. G. Koland, “Epidermal growth factor-dependent association of phosphatidylinositol 3- kinase with the erbB3 gene product,” Journal of Biological Chemistry, vol. 269, no. 40, pp. 24747–24755, 1994.
[141]
S. P. Soltoff, K. L. Carraway III, S. A. Prigent, W. G. Gullick, and L. C. Cantley, “ErbB3 is involved in activation of phosphatidylinositol 3-kinase by epidermal growth factor,” Molecular and Cellular Biology, vol. 14, no. 6, pp. 3550–3558, 1994.
[142]
J. T. Garrett, M. G. Olivares, C. Rinehart et al., “Transcriptional and posttranslational up-regulation of HER3 (ErbB3) compensates for inhibition of the HER2 tyrosine kinase,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 12, pp. 5021–5026, 2011.
[143]
M. Scaltriti, C. Verma, M. Guzman et al., “Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity,” Oncogene, vol. 28, no. 6, pp. 803–814, 2009.
[144]
T. Maruyama, K. Mimura, S. Izawa, A. Inoue, S. Shiba, M. Watanabe, et al., “Lapatinib enhances herceptin-mediated antibody-dependent cellular cytotoxicity by up-regulation of cell surface HER2 expression,” Anticancer Research, vol. 31, pp. 2999–3005, 2011.
[145]
N. Gaborit, C. Larbouret, J. Vallaghe et al., “Time-resolved fluorescence resonance energy transfer (TR-FRET) to analyze the disruption of EGFR/HER2 dimers: a new method to evaluate the efficiency of targeted therapy using monoclonal antibodies,” Journal of Biological Chemistry, vol. 286, no. 13, pp. 11337–11345, 2011.
[146]
M. C. Franklin, K. D. Carey, F. F. Vajdos, D. J. Leahy, A. M. De Vos, and M. X. Sliwkowski, “Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex,” Cancer Cell, vol. 5, no. 4, pp. 317–328, 2004.
[147]
H. S. Cho, K. Mason, K. X. Ramyar et al., “Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab,” Nature, vol. 421, no. 6924, pp. 756–760, 2003.
[148]
D. B. Agus, R. W. Akita, W. D. Fox et al., “Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth,” Cancer Cell, vol. 2, no. 2, pp. 127–137, 2002.
[149]
S. Diermeier-Daucher, M. Hasmann, and G. Brockhoff, “Flow cytometric FRET analysis of erbB receptor interaction on a cell-by-cell basis,” Annals of the New York Academy of Sciences, vol. 1130, pp. 280–286, 2008.
[150]
C. C. Portera, J. M. Walshe, D. R. Rosing et al., “Cardiac toxicity and efficacy of trastuzumab combined with pertuzumab in patients with trastuzumab-insensitive human epidermal growth factor receptor 2-positive metastatic breast cancer,” Clinical Cancer Research, vol. 14, no. 9, pp. 2710–2716, 2008.
[151]
J. Baselga, K. A. Gelmon, S. Verma et al., “Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy,” Journal of Clinical Oncology, vol. 28, no. 7, pp. 1138–1144, 2010.
[152]
J. Baselga, J. Cortes, S. B. Kim, S. A. Im, R. Hegg, Y. H. Im, et al., “Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer,” The New England Journal of Medicine, vol. 366, pp. 109–119, 2012.
[153]
L. Gianni, T. Pienkowski, Y. H. Im, L. Roman, L. M. Tseng, M. C. Liu, et al., “Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial,” The Lancet Oncology, vol. 13, pp. 25–32, 2012.
[154]
R. Nahta, M. C. Hung, and F. J. Esteva, “The HER-2-targeting antibodies trastuzumab and pertuzumab synergistically inhibit the survival of breast cancer cells,” Cancer Research, vol. 64, no. 7, pp. 2343–2346, 2004.
[155]
G. Arpino, C. Gutierrez, H. Weiss et al., “Treatment of human epidermal growth factor receptor 2-overexpressing breast cancer xenografts with multiagent HER-targeted therapy,” Journal of the National Cancer Institute, vol. 99, no. 9, pp. 694–705, 2007.
[156]
W. Scheuer, T. Friess, H. Burtscher, B. Bossenmaier, J. Endl, and M. Hasmann, “Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumor models,” Cancer Research, vol. 69, no. 24, pp. 9330–9336, 2009.
[157]
G. Brockhoff, B. Heckel, E. Schmidt-Bruecken et al., “Differential impact of Cetuximab, Pertuzumab and Trastuzumab on BT474 and SK-BR-3 breast cancer cell proliferation,” Cell Proliferation, vol. 40, no. 4, pp. 488–507, 2007.
[158]
S. T. Lee-Hoeflich, L. Crocker, E. Yao et al., “A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy,” Cancer Research, vol. 68, no. 14, pp. 5878–5887, 2008.
[159]
C. F. McDonagh, A. Huhalov, B. D. Harms, S. Adams, V. Paragas, S. Oyama, et al., “Antitumor activity of a novel bispecific antibody that targets the ErbB2/ErbB3 oncogenic unit and inhibits heregulin-induced activation of ErbB3,” Molecular Cancer Therapeutics, vol. 11, pp. 582–593, 2012.
[160]
P. K. Foreman, M. Gore, P. A. Kobel, L. Xu, H. Yee, C. Hannum, et al., “ErbB3 inhibitory surrobodies inhibit tumor cell proliferation in vitro and in vivo,” Molecular Cancer Therapeutics, vol. 11, pp. 1411–1420, 2012.
[161]
D. Yee, “Insulin-like growth factor receptor inhibitors: baby or the bathwater?” Journal of the National Cancer Institute, vol. 104, pp. 975–981, 2012.
[162]
X. Zeng, D. Sachdev, H. Zhang, M. Gaillard-Kelly, and D. Yee, “Sequencing of type i insulin-like Growth factor receptor inhibition affects chemotherapy response in vitro and in vivo,” Clinical Cancer Research, vol. 15, no. 8, pp. 2840–2849, 2009.
[163]
L. N. Harris, F. You, S. J. Schnitt et al., “Predictors of resistance to preoperative trastuzumab and vinorelbine for HER2-positive early breast cancer,” Clinical Cancer Research, vol. 13, no. 4, pp. 1198–1207, 2007.
[164]
R. Yerushalmi, K. A. Gelmon, S. Leung et al., “Insulin-like growth factor receptor (IGF-1R) in breast cancer subtypes,” Breast Cancer Research and Treatment, vol. 132, pp. 131–142, 2011.
[165]
R. Kumar, M. Mandal, A. Lipton, H. Harvey, and C. B. Thompson, “Overexpression of HER2 modulates bcl-2, Bcl-X(L) and tamoxifen induced apoptosis in human MCP-7 breast cancer cells,” Clinical Cancer Research, vol. 2, no. 7, pp. 1215–1219, 1996.
[166]
J. Shou, S. Massarweh, C. K. Osborne et al., “Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer,” Journal of the National Cancer Institute, vol. 96, no. 12, pp. 926–935, 2004.
[167]
R. Nahta and R. M. O'Regan, “Therapeutic implications of estrogen receptor signaling in HER2-positive breast cancers,” Breast Cancer Research and Treatment, vol. 135, pp. 39–48, 2012.
