Trastuzumab

Chemotherapy-induced cardiotoxicity is an increasing concern and it is critical to avoid heart dysfunction induced by medications used in various cancers. Dysregulated cardiomyocyte homeostasis is a critical phenomenon of drug-induced cardiotoxicity, which hinders the cardiac tissue's natural physiological function. Drug-induced cardiotoxicity is responsible for various heart disorders such as myocardial infarction, myocardial hypertrophy, and arrhythmia, among others. Chronic cardiac stress due to drug toxicity restricts the usage of cancer medications. Anticancer medications can cause a variety of adverse effects, especially cardiovascular toxicity. This review is focused on anticancerous drugs anthracyclines, trastuzumab, nonsteroidal anti-inflammatory medications (NSAIDs), and immune checkpoint inhibitors (ICI) and associated pathways attributed to the drug-induced cardiotoxicity. Several factors responsible for enhanced cardiotoxicity are age, gender specificity, diseased conditions, and therapy are also discussed. The review also highlighted the patents assigned for different methodologies involved in the assessment and reducing cardiotoxicity. Recent advancements where the usage of trastuzumab and bevacizumab have caused cardiac dysfunction and their effects alone or in combination on cardiac cells are explained. Extensive research on patents associated with protection against cardiotoxicity has shown that chemicals like bis(dioxopiperazine)s and manganese compounds were cardioprotective when combined with other selected anticancerous drugs. Numerous patents are associated with druginduced toxicity, prevention, and diagnosis, that may aid in understanding the current issues and developing novel therapies with safer cardiovascular outcomes. Also, the advancements in technology and research going on are yet to be explored to overcome the present issue of cardiotoxicity with the development of new drug formulations.

Trastuzumab resistance in HER2+ breast cancer (BC) is the major reason leading to poor prognosis of BC patients. Oncogenic gene overexpression or aberrant activation of tyrosine kinase SRC is identified to be the key modulator of trastuzumab response. However, the detailed regulatory mechanisms underlying SRC activation-associated trastuzumab resistance remain poorly understood. In the present study, we discover that SRC-mediated YAP1 tyrosine phosphorylation facilitates its interaction with transcription factor AP-2 alpha (activating enhancer binding protein 2 alpha, TFAP2A), which in turn promotes YAP1/TEAD-TFAP2A (YTT) complex-associated transcriptional outputs, thereby conferring trastuzumab resistance in HER2+ BC. Inhibition of SRC kinase activity or disruption of YTT complex sensitizes cells to trastuzumab treatment in vitro and in vivo. Additionally, we also identify YTT complex co-occupies the regulatory regions of a series of genes related to trastuzumab resistance and directly regulates their transcriptions, including EGFR, HER2, H19 and CTGF. Moreover, YTT-mediated transcriptional regulation is coordinated by SRC kinase activity. Taken together, our study reveals that SRC-mediated YTT complex formation and transcriptions are responsible for multiple mechanisms associated with trastuzumab resistance. Therefore, targeting HER2 signaling in combination with the inhibition of YTT-associated transcriptional outputs could serve as the treatment strategy to overcome trastuzumab resistance caused by SRC activation.