Triple-negative breast cancer (TNBC) is an aggressive
cancer that lacks specific molecular targets that are often used for
therapy. The refractory rate of TNBC to broad-spectrum
chemotherapy remains high; however, the combination of newly developed treatments with the current standard of care has delivered promising anti-
tumor effects. One mechanism employed by TNBC to avoid cell death is the increased expression of the
anti-apoptotic protein, myeloid cell
leukemia 1 (MCL1). Multiple studies have demonstrated that increased MCL1 expression enables resistance to
platinum-based
chemotherapy. In addition to suppressing apoptosis, we recently demonstrated that MCL1 also binds and negatively regulates the transcriptional activity of TP73. TP73 upregulation is a critical driver of
cisplatin-induced DNA damage response, and ultimately, cell death. We therefore sought to determine if the coadministration of an MCL1-targeted inhibitor with
cisplatin could produce a synergistic response in TNBC. This study demonstrates that the MCL1 inhibitor,
S63845, combined with
cisplatin synergizes by inducing apoptosis while also decreasing proliferation in a subset of TNBC cell lines. The use of combined MCL1 inhibitors with
cisplatin in TNBC effectively initiates TAp73 anti-
tumor effects on cell cycle arrest and apoptosis. This observation provides a molecular profile that can be exploited to identify sensitive TNBCs.