Despite promising anti-leukemic activity of MCL-1 inhibitors in preclinical studies of acute myeloid leukemia (AML), clinical progress has been hindered by limited knowledge of target patient subgroups. To stratify patients for MCL-1 inhibitor treatment, we evaluated the sensitivity of 42 primary AML samples to MCL-1 inhibitor MIK665 (S64315) and analyzed their molecular profiles. We observed that MIK665-sensitive samples had a more differentiated phenotype, whereas resistant samples displayed higher levels of ABCB1 (MDR1) and the anti-apoptotic protein BCL-XL. Moreover, ABCB1 expression had good predictive performance in identifying resistant samples. To induce sensitivity, we treated MIK665-resistant samples with ABCB1 inhibitors elacridar or tariquidar, BCL-XL inhibitor A1331852, or BCL-2 inhibitor venetoclax in combination with MIK665. The combination of MIK665 with each of elacridar, tariquidar, or venetoclax effectively eliminated AML blasts compared to the agents alone, while the combination with A1331852 showed limited efficacy for this patient subgroup. Additionally, the combination of MIK665 with venetoclax restored sensitivity in samples with primary venetoclax resistance. Overall, this study indicates that elevated ABCB1 expression is a potentially targetable resistance mechanism in the context of MIK665 resistance, and that a combination of MIK665 with venetoclax may be effective for overcoming resistance to either MCL-1 or BCL-2 inhibition.
Keywords: MCL‐1 inhibition; acute myeloid leukemia; apoptosis; combination therapies; multidrug resistance‐associated proteins; prognostic biomarkers.
© 2025 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.