SorLA Targeting - A Method to Overcome Therapy Resistance in Breast Cancer

Abstract

Tyrosine kinase-type cell surface receptor HER2targeted therapies have dramatically improved breast cancer patients’ outcome compared to conventional chemotherapies. In the clinic, HER2 monoclonal antibody trastuzumab with chemotherapy represent the gold standard treatment of HER2-positive breast cancer [1]. In the advanced metastatic setting, other Federation of Drug Administration (FDA)-approved HER2-based therapeutic options are used such as HER2 small molecule tyrosine kinase inhibitor neratinib [2]. Metastatic tumors are often therapy-resistant due to drug resistance mechanisms leading to sustained cancer progression most notably with regard to brain metastatic breast cancer, the most challenging medical-oncology situation [3]. 50% of brain metastatic HER2-positive breast cancer samples exhibit enriched HER3 expression compared to their matched primary tumors [4]. Elevated HER3 levels is one of the most reported therapy-resistance mechanisms in breast cancer [5]. HER3 lacks a fully active intracellular kinase domain, however, upon ligand binding the receptor heterodimerizes with its favorite partner HER2 that adopts constitutively the open conformation required for receptor dimerization [6]. The HER2-HER3 heterodimer is a unique and powerful signaling unit facilitating signaling such that even a residual HER2 activation is sufficient to trans-phosphorylate HER3 that bears at least six direct docking sites for the p85 adaptor subunit of phosphoinositide 3-kinase [5,6]. This enables HER3 to compensate for HER2 inhibition and renders HER2-HER3 the most signaling-effective component among all the different heterodimers within the HER family [6,7]. HER3 inhibition is an unmet clinical need since the extensive preclinical and clinical efforts targeting this receptor have thus far failed to lead to FDA approval in any cancer type. This is partly owing to the fact that targeting HER3 using classic tyrosine kinase inhibitors is not an option [5].