Predictors of Response and Rational Combinations for the Novel MCL-1 Inhibitor MIK665 in Acute Myeloid Leukemia

Despite promising anti-leukemic activity of MCL-1 inhibitors in preclinical studies of acute myeloid leukemia (AML), their progress through clinical evaluation has in part been challenged by limited knowledge of patient subgroups suitable for treatment. To stratify patients with AML for MCL-1 inhibitor-based treatment, we evaluated the sensitivity of 42 primary AML samples to MCL-1 inhibitor MIK665 (S64315) and contrasted 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. Further evaluation revealed that ABCB1 expression has good predictive performance in identifying MIK665 primary resistant samples. To induce sensitivity, we treated MIK665-resistant samples with ABCB1 inhibitor elacridar, BCL-XL inhibitor A1331852, or BCL-2 inhibitor venetoclax in combination with MIK665. While combinations with elacridar and A1331852 were not effective, the combination of MIK665 and venetoclax effectively eliminated AML blasts compared to either of the agents alone. Additionally, the combination restored sensitivity of samples with primary venetoclax resistance. Overall, this study indicates that elevated ABCB1 expression is a potential predictor of resistance to MIK665 in AML, and that a combination of MIK665 with venetoclax may be effective for overcoming resistance to either MCL-1 or BCL-2 inhibition.