Implications of Autophagy and Oxidative Stress in Trastuzumab-Mediated Cardiac Toxicities

Trastuzumab, a humanized monoclonal antibody directed against human epidermal growth factor receptor 2 (HER2), remains the standard of care as part of adjuvant therapy for patients diagnosed with HER2-positive breast cancers. Despite high therapeutic efficacy, trastuzumab-based regimens can cause serious cardiotoxic side effects. Effective mitigation of cardiotoxic risk relies on thorough understanding of molecular mechanisms of cardiotoxicity induced by trastuzumab. Among the probable mechanisms responsible for trastuzumab-mediated cardiotoxicity, generation of free radicals causing oxidative stress has garnered notable attention in recent years. More recently, role of autophagy in trastuzumab-induced cardiomyopathy was explored. Trastuzumab-mediated HER2 signaling dysregulation activated Erk/mTOR signaling cascade resulting in autophagy inhibition. Consequently, autophagy impairment leads to massive accumulation of damaged mitochondria and free radicals causing oxidative stress and toxicity in cardiomyocytes. This review will discuss recent advances in understanding the mechanism of oxidative stress and highlight the role of autophagy in trastuzumab-mediated cardiac dysfunctions.