Trastuzumab Resistance, a Potential Roadblock for Most Successful Therapy of Breast Cancer—An Updated Review of Underlying Mechanisms, Clinical Trials and Patents to Evade the Resistance

Trastuzumab is the first humanised monoclonal antibody (Mab) developed for breast cancer (BC) therapy. The high affinity of Trastuzumab Fab-domain binding to the human epidermal growth factor receptor 2 (HER2) receptor, with a Kd value of <1 nM, is also accompanied by Fc domain interaction with Fc-receptors in natural killer cells and leukocytes, enabling the killing of tumour cells through antibody-directed cellular cytotoxicity (ADCC). Trastuzumab blocks the over-expressed HER2 receptor-mediated dimerization and consequent intracellular signalling, leading to cancerous growth. However, the trastuzumab resistance (TR) became the major problem within 1 year of treatment. The mutation in phosphatidylinositol 3′-kinase (PI3K) pathway, cross-talk with estrogen receptors, over-expression of Mucin 1 (MUC1) protein, insulin-like growth factor I receptor, etc., are key pathways involved in TR. In this review, we have provided a molecular view of TR and the possible remedies for overcoming TR using BC stem cell (BCSC)-based therapy, PI3K pathway inhibitors, MUC1-based treatment, etc. We have also analysed the patents and clinical trials from the pre-TR and post-TR era to rationalise the possible steps to overcome TR. Our analysis implies that Trastuzumab monotherapy no longer applies to HER2+ BC treatment. Further, combination therapy using other antibodies like pertuzumab and protein kinase inhibitors and targeting pathways like the ubiquitin proteasome pathway will be the future option for BC Treatment. Overall, this review provides a detailed summary of the molecular mechanisms involving TR and its potential ways of evasion, based on updated information from published research articles, clinical trial outcomes, and patent data.