Elevation of Receptor Tyrosine Kinase EphA2 Mediates Resistance to Trastuzumab Therapy

Cancer Research - Tập 70 Số 1 - Trang 299-308 - 2010
Guanglei Zhuang1,2, Dana M. Brantley‐Sieders1,2, David Vaught1,2, Jian Yu1,2, Lu Xie1,2, Sam Wells1,2, Dowdy Jackson1,2, Rebecca S. Muraoka-Cook1,2, Carlos L. Arteaga1, Jin Chen1
1Authors' Affiliations: 1Department of Cancer Biology, 2Division of Rheumatology and Immunology, Department of Medicine, 3Department of Cell and Developmental Biology, 4Vanderbilt-Ingram Cancer Center, and 5Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tenessee; 6Shanghai Center for Bioinformation Technology, Shanghai, P.R. China; and 7MedImmune, LLC, Gaithersburg, Maryland
2MedImmune, LLC, Gaithersburg, Maryland

Tóm tắt

Abstract One arising challenge in the treatment of breast cancer is the development of therapeutic resistance to trastuzumab, an antibody targeting the human epidermal growth factor receptor-2 (HER2), which is frequently amplified in breast cancers. In this study, we provide evidence that elevated level of the receptor tyrosine kinase Eph receptor A2 (EphA2) is an important contributor to trastuzumab resistance. In a screen of a large cohort of human breast cancers, we found that EphA2 overexpression correlated with a decrease in disease-free and overall survival of HER2-overexpressing patients. Trastuzumab-resistant cell lines overexpressed EphA2, whereas inhibiting EphA2 restored sensitivity to trastuzumab treatment in vivo. Notably, trastuzumab treatment could promote EphA2 phosphorylation by activating Src kinase, leading in turn to an amplification of phosphoinositide 3-kinase/Akt and mitogen-activated protein kinase signaling in resistant cells. Our findings offer mechanistic insights into the basis for trastuzumab resistance and rationalize strategies to target EphA2 as a tactic to reverse trastuzumab resistance. Cancer Res; 70(1); 299–308.

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Tài liệu tham khảo

Carter, 1992, Humanization of an anti-p185HER2 antibody for human cancer therapy, Proc Natl Acad Sci U S A, 89, 4285, 10.1073/pnas.89.10.4285

Hudis, 2007, Trastuzumab—mechanism of action and use in clinical practice, N Engl J Med, 357, 39, 10.1056/NEJMra043186

Baselga, 1996, Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer, J Clin Oncol, 14, 737, 10.1200/JCO.1996.14.3.737

Cobleigh, 1999, 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, J Clin Oncol, 17, 2639, 10.1200/JCO.1999.17.9.2639

Vogel, 2002, Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer, J Clin Oncol, 20, 719, 10.1200/JCO.2002.20.3.719

Slamon, 2001, Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2, N Engl J Med, 344, 783, 10.1056/NEJM200103153441101

Vaught, 2008, Eph receptors in breast cancer: roles in tumor promotion and tumor suppression, Breast Cancer Res, 10, 217, 10.1186/bcr2207

Pasquale, 2008, Eph-ephrin bidirectional signaling in physiology and disease, Cell, 133, 38, 10.1016/j.cell.2008.03.011

Wykosky, 2008, The EphA2 receptor and ephrinA1 ligand in solid tumors: function and therapeutic targeting, Mol Cancer Res, 6, 1795, 10.1158/1541-7786.MCR-08-0244

Duxbury, 2004, EphA2: a determinant of malignant cellular behavior and a potential therapeutic target in pancreatic adenocarcinoma, Oncogene, 23, 1448, 10.1038/sj.onc.1207247

Zelinski, 2001, EphA2 overexpression causes tumorigenesis of mammary epithelial cells, Cancer Res, 61, 2301

Fang, 2005, A kinase-dependent role for EphA2 receptor in promoting tumor growth and metastasis, Oncogene, 24, 7859, 10.1038/sj.onc.1208937

Landen, 2005, Therapeutic EphA2 gene targeting in vivo using neutral liposomal small interfering RNA delivery, Cancer Res, 65, 6910, 10.1158/0008-5472.CAN-05-0530

Nasreen, 2006, Silencing the receptor EphA2 suppresses the growth and haptotaxis of malignant mesothelioma cells, Cancer, 107, 2425, 10.1002/cncr.22254

Chen, 2008, Eph receptors and Ephrins in cancer: common themes and controversies, Cancer Res, 68, 10031, 10.1158/0008-5472.CAN-08-3010

Larsen, 2007, Activation of the EGFR gene target EphA2 inhibits epidermal growth factor-induced cancer cell motility, Mol Cancer Res, 5, 283, 10.1158/1541-7786.MCR-06-0321

Brantley-Sieders, 2008, The receptor tyrosine kinase EphA2 promotes mammary adenocarcinoma tumorigenesis and metastatic progression in mice by amplifying ErbB2 signaling, J Clin Invest, 118, 64, 10.1172/JCI33154

Rody, 2009, Loss of Plexin B1 is highly prognostic in low proliferating ER positive breast cancers—results of a large scale microarray analysis, Eur J Cancer, 45, 405, 10.1016/j.ejca.2008.10.016

Rody, 2009, T-cell metagene predicts a favorable prognosis in estrogen receptor-negative and HER2-positive breast cancers, Breast Cancer Res, 11, R15, 10.1186/bcr2234

Alexe, 2007, High expression of lymphocyte-associated genes in node-negative HER2+ breast cancers correlates with lower recurrence rates, Cancer Res, 67, 10669, 10.1158/0008-5472.CAN-07-0539

Muraoka, 2003, Increased malignancy of Neu-induced mammary tumors overexpressing active transforming growth factor β1, Mol Cell Biol, 23, 8691, 10.1128/MCB.23.23.8691-8703.2003

Ritter, 2007, Human breast cancer cells selected for resistance to trastuzumab in vivo overexpress epidermal growth factor receptor and ErbB ligands and remain dependent on the ErbB receptor network, Clin Cancer Res, 13, 4909, 10.1158/1078-0432.CCR-07-0701

Nahta, 2005, Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells, Cancer Res, 65, 11118, 10.1158/0008-5472.CAN-04-3841

Debnath, 2003, Morphogenesis and oncogenesis of MCF-10A mammary epithelial acini grown in three-dimensional basement membrane cultures, Methods, 30, 256, 10.1016/S1046-2023(03)00032-X

Brantley-Sieders, 2005, Impaired tumor microenvironment in EphA2-deficient mice inhibits tumor angiogenesis and metastatic progression, FASEB J, 19, 1884, 10.1096/fj.05-4038fje

van de Vijver, 2002, A gene-expression signature as a predictor of survival in breast cancer, N Engl J Med, 347, 1999, 10.1056/NEJMoa021967

Carter, 2002, EphrinA1-induced cytoskeletal re-organization requires FAK and p130(cas), Nat Cell Biol, 4, 565, 10.1038/ncb823

Muthuswamy, 2001, ErbB2, but not ErbB1, reinitiates proliferation and induces luminal repopulation in epithelial acini, Nat Cell Biol, 3, 785, 10.1038/ncb0901-785

Belsches-Jablonski, 2001, Src family kinases and HER2 interactions in human breast cancer cell growth and survival, Oncogene, 20, 1465, 10.1038/sj.onc.1204205

Kim, 2005, The c-Src tyrosine kinase associates with the catalytic domain of ErbB-2: implications for ErbB-2 mediated signaling and transformation, Oncogene, 24, 7599, 10.1038/sj.onc.1208898

Nagata, 2004, PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients, Cancer Cell, 6, 117, 10.1016/j.ccr.2004.06.022

Ouyang, 2008, Determination of hierarchical relationship of Src and Rac at subcellular locations with FRET biosensors, Proc Natl Acad Sci U S A, 105, 14353, 10.1073/pnas.0807537105

Wang, 2005, Visualizing the mechanical activation of Src, Nature, 434, 1040, 10.1038/nature03469

Hynes, 2005, ERBB receptors and cancer: the complexity of targeted inhibitors, Nat Rev Cancer, 5, 341, 10.1038/nrc1609

Nahta, 2006, Mechanisms of disease: understanding resistance to HER2-targeted therapy in human breast cancer, Nat Clin Pract Oncol, 3, 269, 10.1038/ncponc0509

Berns, 2007, A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer, Cancer Cell, 12, 395, 10.1016/j.ccr.2007.08.030

Lu, 2001, Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (Herceptin), J Natl Cancer Inst, 93, 1852, 10.1093/jnci/93.24.1852

Gori, 2009, EGFR, pMAPK, pAkt and PTEN status by immunohistochemistry: correlation with clinical outcome in HER2-positive metastatic breast cancer patients treated with trastuzumab, Ann Oncol, 20, 648, 10.1093/annonc/mdn681

Hosokawa, 2009, Comprehensive analysis of EGFR signaling pathways in Japanese patients with non-small cell lung cancer, Lung Cancer, 66, 107, 10.1016/j.lungcan.2009.01.005

Carracedo, 2008, Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer, J Clin Invest, 118, 3065

Grant, 2008, Cotargeting survival signaling pathways in cancer, J Clin Invest, 118, 3003, 10.1172/JCI36898E1

Kinkade, 2008, Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model, J Clin Invest, 118, 3051

Moulder, 2001, Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/neu (erbB2)-overexpressing breast cancer cells in vitro and in vivo, Cancer Res, 61, 8887

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Cancer Research

Tập 70 Số 1

299-308

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