RESISTANCE TO ANTI-HER2 AGENTS

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Abstract

∼20% of breast cancers are characterized by overexpression of human epidermal growth factor receptor 2 (HER2) protein and associated gene amplification, and the receptor tyrosine kinase (RTK) is believed to play a critical role in the pathogenesis of these tumors. Trastuzumab, a humanized monoclonal antibody against the extracellular domain of HER2 protein, and lapatinib, a small molecule tyrosine kinase inhibitor against HER1/HER2, has significantly improved treatment outcomes in patients with HER2-overexpressing breast cancer. Many other anti-HER2 agents are also now under clinical development. In parallel with this clinical development, primary and acquired resistance to these agents has been vigorously studied. For trastuzumab in particular, numerous potential mechanisms of resistance have been proposed. These include impaired access of trastuzumab to HER2 by expression of extracellular domain-truncated HER2 (p95 HER2) or overexpression of MUC4; alternative signaling from insulin-like growth factor-1 receptor, other epidermal growth factor receptor (EGFR) family members, or MET; aberrant downstream signaling caused by loss of phosphatase and tensin homologs deleted from chromosome 10 (PTEN), PIK3CA mutation, or downregulation of p27; and FCGR3A polymorphisms. With regard to lapatinib, while this agent has been proven to overcome some trastuzumab resistance both pre-clinically and clinically, its resistance mechanisms have also been studied extensively. Proposed mechanisms include alternative signaling from another RTK, AXL or fibroblast growth factor receptor 2 (FGFR2), PIK3CA mutation, migration of survival signal to estrogen receptor (ER) signals, and activation of RelA. In the symposium, these mechanisms will be overviewed and potential therapeutic strategies for overcoming them will be discussed.

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