MCL1 Small Molecule Inhibitor S63845 Synergizes with Cisplatin in Basal-like Triple Negative Breast Cancer

Abstract

Triple negative breast cancer (TNBC) is an aggressive cancer that lacks specific molecular targeted therapies. Thus, current standard of care requires the use of neoadjuvant therapy with taxol, cytoxan, and platinum-based agents. There is a strong therapeutic resistance to platinum-based therapy, thus combination of multiple treatments has confirmed promising anti-tumorous effects for TNBC. The ability to avoid cell death can be attributed increased expression of the anti-apoptotic protein, myeloid cell leukemia 1 (MCL1). Multiple studies have demonstrated that MCL1 enables resistance to chemotherapy and directly correlates with increased tumor size and invasion. We recently demonstrated that MCL1 binds to the DNA damage response protein, p73, and suppresses its transcriptional activity. As p73 upregulation is a key mechanism for cisplatin induced DNA damage response and ultimately cell death, we sought to determine if coadministration of a MCL1 targeted inhibitor with cisplatin would produce a synergistic response in TNBC. This study demonstrates that the MCL1 inhibitor, S63845, combined with cisplatin synergizes in basallike TNBC cell lines. Additionally, basal-like lines treated with this combination showed a significant increase in TAp73 mRNA expression as well as downstream targets where this observation was absent in mesenchymal TNBC. This observation provides a molecular profile for use of combined MCL1 inhibitors with cisplatin in basal-like TNBC as inhibition of MCL1 effectively initiates TAp73 anti-tumorous effect on cell cycle arrest and apoptosis. Support/Funding Information: R01GM117391