Mechanisms underlying Trastuzumab Resistance in HER2-positive (HER2+) Breast Cancer and potential therapeutic approaches

Abstract

HER2-positive (HER2+) breast cancer is characterized by overexpression of HER2 (Human Epidermal Growth Factor Receptor 2) protein on the surface of cells in the breast's ducts or lobes. HER2 overexpression creates an overabundance of homo- and/or heterodimers with other family members, and triggers activation of PI3K/Akt and MAPK signalling pathways, resulting in uncontrolled cell growth and proliferation. Past studies have shown that HER2 overexpression correlates with aggressiveness, higher relapse risk, and poor long-term survival. The incorporation of the monoclonal antibody trastuzumab into chemotherapy has dramatically improved treatments. Trastuzumab prevents HER2 homo- and/or heterodimerization, and promotes HER2 endocytosis, ubiquitination, and proteolytic degradation, resulting in inhibition of the HER2 signalling pathway and HER2-induced cellular responses. However, trastuzumab resistance which mainly develops in the metastatic setting, is a major clinical problem. This bibliographical review primarily focuses on presenting three molecular mechanisms, through which trastuzumab resistance arises leading to continuous activation of the HER2 signalling pathway. The first mechanism involves overexpression of CMTM6, leading to decreased HER2 ubiquitination, resulting in increased cell viability, proliferation and invasion, and decreased apoptosis. The second mechanism involves underexpression of CMTM7, caused by miR-182-5p and leading to Rab-5A inactivation, resulting in the prevention of HER2 degradation. The third mechanism involves the overexpression of TRAF4 E3 ubiquitin ligase that prevents SMURF2 E3 ubiquitin ligase from interacting and ubiquitinating HER2, resulting in continuous activation of the HER2 signalling pathway and increased cell viability and tumour volume. In addition, this review discusses several therapeutic approaches to overcome trastuzumab resistance, including a) the use of adavosertib to reduce CMTM6 expression, b) the use of the miR-182-5p inhibitor to prevent the reduction of CMTM7 expression and c) β-escin, as an alternative drug. Currently, approved therapies are focused on the use of trastuzumab in combination with pertuzumab or ado-trastuzumab emtansine (T-DM1) antibodies. This review showed that continued research to identify the optimal combined therapy holds promise for enhancing overall survival in HER2+ breast cancer patients.