Myeloid Cell Leukemia 1 Small Molecule Inhibitor S63845 Synergizes with Cisplatin in Triple-Negative Breast Cancer

Simple Summary This manuscript builds on our recent observations that the cell-death-suppressing protein, MCL1, is able to directly regulate the DNA damage response transcription factor TP73. TP73, a homolog of TP53, is known to be activated following treatment with the anti-cancer drug, cisplatin. We therefore sought to determine if emerging anti-cancer drugs that target MCL1 combine with cisplatin in a synergistic fashion. This study provides a molecular mechanism for the prior observation that MCL1 expression can impact cisplatin sensitivity. Further, our work establishes a profile to guide further exploration of combination therapies that combine DNA damaging agents with anti-apoptotic BCL2 family inhibitors.Abstract 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.