Abstract 1854: Selective Mcl-1 inhibition with KS18 overcomes apoptotic resistance and enhances FLT3-targeted therapy in acute myeloid leukemia.

Abstract Acute myeloid leukemia (AML) remains the most common adult leukemia and continues to have a dismal 5-year survival rate below 30 percent, largely due to relapse driven by therapy-resistant leukemic clones. Overexpression of the anti-apoptotic protein Mcl-1 is a major mechanism of such resistance, particularly against FLT3 and BCL-2 inhibitors, making selective Mcl-1 blockade a compelling therapeutic strategy. Here, we evaluate KS18, a highly selective small-molecule Mcl-1 inhibitor developed in our laboratory, as a single agent and in rational drug combinations in AML models (MOLM-13, MV4-11, THP-1) including a venetoclax-resistant line (MV4-11 VR). KS18 potently restored intrinsic apoptotic signaling by targeting the BH3-binding groove of Mcl-1 and releasing bound pro-apoptotic effectors (BIM, BAK, BAX), resulting in mitochondrial outer membrane permeabilization, cytochrome-c release, and robust caspase-dependent apoptosis. Mechanistically, KS18 induced mitochondrial dysfunction as evidenced by altered oxygen consumption (OCR) and extracellular acidification (ECAR) profiles. Combination treatment with either the FLT3 inhibitor quizartinib or the multi-kinase inhibitor sitravatinib yielded strong synergistic cytotoxicity through concurrent Mcl-1 suppression and inhibition of upstream survival pathways including FLT3/STAT5, AKT, and ERK. These combinations markedly enhanced cleaved caspase-3 and PARP levels, confirming extensive mitochondrial apoptosis. Together, these findings identify KS18 as a promising next-generation therapeutic candidate with both single-agent efficacy and strong combination potential for overcoming drug resistance and relapse in AML. Ongoing studies are generating FLT3 inhibitor-resistant models and evaluating KS18 in vivo across diverse FLT3 mutation backgrounds to accelerate its translational development for relapsed and refractory AML. Citation Format: Sahil Jethi, Krishne Gowda, Tulin Budak-Alpdogan, Subash C. Jonnalagadda, Manoj K. Pandey. Selective Mcl-1 inhibition with KS18 overcomes apoptotic resistance and enhances FLT3-targeted therapy in acute myeloid leukemia abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1854.