Mechanisms contributing to ado-trastuzumab emtansine-induced toxicities: a gateway to better understanding of ADC-associated toxicities
Yukinori Endo, Nishant Mohan, Milos Dokmanovic, Wen Jin Wu
Abstract
In order to improve the safety of novel therapeutic drugs, better understanding of the mechanisms of action is important. Ado-trastuzumab emtansine (also known as T-DM1) is an antibody-drug conjugate (ADC) approved for the treatment of HER2-positive breast cancer. While the treatment with T-DM1 results in significant efficacy in the selected patient population, nonetheless, there are concerns with side effects such as thrombocytopenia and hepatotoxicity. While current understanding of the mechanism of T-DM1-mediated side effects is still incomplete, there have been several reports of HER2-dependent and/or -independent mechanisms that could be associated with the T-DM1-induced adverse events. This review highlights the importance of HER2-independent mechanism of T-DM1 to induce hepatotoxicity, which offers a new insight into a role for CKAP5 in the overall maytansinoid-based ADC (DM1 and DM4)-mediated cytotoxicity. This discovery provides a molecular basis for T-DM1-induced off-target toxicity and opens a new avenue for developing the next generation of ADCs.