LAUSR

Recent advancements in multiple myeloma (MM) therapy have not changed the fact that it is incurable, and all patients experience relapse or become refractory. Thus, more effective treatments are needed to prolong the survival of MM patients. Anti-apoptotic myeloid cell leukemia 1 (Mcl-1) overexpression is correlated with poor prognosis and drug resistance in MM. Nonetheless, there is a lack of effective Mcl-1 inhibitors. To address this unmet clinical need, we developed KS18, a Mcl-1 inhibitor. We generated respective resistant cells to investigate whether KS18 may overcome acquired resistance against various available drugs in the clinic including bortezomib, venetoclax, and ABT-737. KS18 was effective against all MM cells with IC50 values ranging between 1.5 to 2.5µM. KS18 showed significant Mcl-1 inhibition in various MM cells including resistant cells. Importantly, KS18 re-sensitizes resistant cells to bortezomib and other chemotherapeutic drugs. Moreover, KS18 was able to enhance the anti-myeloma activity of venetoclax and ABT-737 treatments toward bortezomib-resistant cells. These results indicate that KS18 possesses the potential to overcome resistance by targeting Mcl-1. Our future studies in patient samples and in vivo model are proposed for further preclinical assessment of this exciting molecule. Citation Format: Omar S. Al Odat, Krishne Gowda, Shantu G. Amin, Tulin Budak- Alpdogan, Subash C. Jonnalagadda, Manoj K. Pandey. Mcl-1 inhibitor KS18 overcomes bortezomib, venetoclax, and ABT-737 resistance in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1748.