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Trastuzumab-mediated Cardiotoxicity: Current Understanding, Challenges, and Frontiers

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Trastuzumab-mediated Cardiotoxicity: Current Understanding, Challenges, and Frontiers

Nishant Mohan et al. Antib Ther.

Abstract

Trastuzumab, an epidermal growth factor receptor 2 (HER2) targeting humanized monoclonal antibody, has been approved for the treatment HER2-positive breast cancer and HER2-positve metastatic gastric cancer. However, cardiotoxicity associated with its clinical application poses challenges for clinicians and patients, mechanisms of which are still evolving. This review will summarize the current mechanistic understanding of trastuzumab-mediated cardiotoxicity, discuss the novel role of DNA topoisomerase IIB as a shared target for enhanced cardiotoxicity induced by trastuzumab and anthracyclines-based combination regimens, and speculate the potential impact of trastuzumab intervention in immune checkpoint inhibitors-based therapies.

Keywords: HER2; TOP2B; cardiotoxicity; trastuzumab.

Figures

Figure 1.
Figure 1.
TOP2B: a shared target for the cardiotoxicity induced by doxorubicin and trastuzumab. Both of doxorubicin and trastuzumab inhibit TOP2B in human cardiomyocytes. Their combined cardiotoxic effect at the cellular level is associated with increased ROS production and DNA damage enhancement. While doxorubicin inhibits TOP2 activity, it also enhances the levels of HER2 expression in human cardiomyocytes, which may render the cardiomyocytes to become addicted to HER2 signaling for survival under stressed conditions, leading to cardiomyocytes becoming more sensitive to trastuzumab treatment after doxorubicin exposure. Our proposed model explains the elevated cardiotoxicity induced by trastuzumab and doxorubicin combination therapy. In addition, Rac1, a small GTPase inhibitor, prevents trastuzumab from inducing DNA damage and suppresses increased ROS production induced by either trastuzumab alone or combination of doxorubicin and trastuzumab, suggesting that Rac1 inhibitor may be used to antagonize cardiotoxicity induced by trastuzumab or trastuzumab and doxorubicin combination therapy.

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