IS5–3 - HER2I Resistance

Abstract

HER2 (ErbB2) is a member of the ErbB family of transmembrane receptor tyrosine kinases, which also includes the epidermal growth factor receptor (EGFR, ErbB1), HER3 (ErbB3) and HER4 (ErbB4). Given HER2 functions as an oncogene, gene amplification induces protein over-expression in cell membranes and regulates signal transduction in cellular processes, such as proliferation, differentiation, and cell survival. Aberrant HER2 expression or function has been associated in carcinogenesis of breast, gastric, ovarian, salivary gland, prostate and lung tumors. In particular HER2 overexpression or HER2 gene amplification has been reported in about 25% of breast cancers and is associated with aggressive disease. The use of anti-HER2 drugs, such as the monoclonal antibody trastuzumab and the TKI (tyrosin-kinase inhibitors) lapatinib, have changed the natural history of HER2-overexpressing breast cancer. Recently, trastuzumab efficacy has been demonstrated also in HER2-positive advanced gastric cancer. However, therapeutic resistance to trastuzumab or lapatinib, as either single-agents or in combination with chemotherapy in the metastatic setting, typically occurs within months of starting therapy. Several mechanisms of trastuzumab resistance have been reported including presence of truncated forms of HER2, as p95HER-2, phosphoinositide 3-kinase pathway activation or signaling pathway activation driven by HER3, epidermal growth factor receptor, and insulin-like growth factor 1 receptor. Alternative anti-HER2 strategies are currently in clinical development to overcome trastuzumab resistance. The use of antibody-drug conjugate is one of these strategies. Trastuzumab-DM1 (T-DM1) is a drug in which trastuzumab is linked to DM1, an antimicrotubule agent, enabling additional delivery of the cytotoxic to targeted cells. Pertuzumab is a recombinant humanized monoclonal antibody that binds to the dimerization epitope of HER-2, blocking its heterodimerization with EGFR and HER-3. Other strategies include: mTOR inhibitors, multi-HER TKIs as Neratinib, IGF-1R inhibitors, EGFR inhibitors and HSP-90 inhibitors.