Trastuzumab Resistance, a Potential Roadblock to the Most Successful Therapy for Breast Cancer – a Review of Underlying Mechanisms with Relevant Patents and Clinical Trials to Overcome the Resistance

In the 1980s, the discovery of a 185 KDa transmembrane human receptor protein which is now known as human epidermal growth factor receptor 2 (HER2), paved the way for the development of the most successful and 1st humanized monoclonal antibody, Trastuzumab. The antibody received FDA and EU approval in 1998 and 2000, respectively for the treatment of patients with HER2+ breast cancer (BC). The high affinity of Trastuzumab binding with HER2 having a Kd value of < 1 nM is due to the dual action of two antibody domains. Here, the Fab domain provides selective binding with the HER2 receptor whereas the Fc domain binds with the Fc receptor in natural killer cells and leukocytes to kill the tumour cells by antibody-directed cellular cytotoxicity (ADCC). Trastuzumab is widely used for the treatment of BC where it blocks the over-expressed HER2 receptor-mediated dimerization and consequent intracellular signaling that leads to cancerous growth. The phosphatidylinositol 3′-kinase (PI3K)/protein kinase B (PKB)/mammalian target of rapamycin pathway (mTOR), cross-talk with estrogen receptors, over-expression of Mucin 1 (MUC1) protein, and involvement of tyrosine kinase receptors like insulin-like growth factor I receptor are key pathways involved in trastuzumab resistance (TR). In this review, we have provided a molecular view of how this resistance appears, and what are the possible remedies using BC stem cell (BCSC)-based therapy, PI3K pathway inhibitors, MUC1-directed therapy, etc. We have also elaborated on the claims from different patents and data from clinical trials where overcoming the TR is one of the primary focuses of those studies.