A Novel MCL-1 Inhibitor Combined with Venetoclax Rescues Venetoclax Resistant Acute Myelogenous Leukemia [Research Articles]

Suppression of apoptosis by expression of anti-apoptotic BCL2-family members is a hallmark of acute myeloblastic leukemia (AML). Induced myeloid leukemia cell differentiation protein (MCL-1), an anti-apoptotic BCL-2 family member, is commonly upregulated in AML cells, and is often a primary mode of resistance to treatment with the BCL-2 inhibitor, venetoclax. Here, we describe VU661013, a novel, potent, selective MCL-1 inhibitor that de-stabilizes BIM/MCL-1 association, leads to apoptosis in AML, and is active in venetoclax-resistant cells and patient derived xenografts. In addition, VU661013 was safely combined with venetoclax for synergy in murine models of AML. Importantly, BH3 profiling of patient samples, and drug sensitivity testing ex vivo accurately predicted cellular responses to selective inhibitors of MCL-1 or BCL-2, and showed benefit of the combination. Taken together, these data suggest a strategy of rationally employing BCL-2 and MCL-1 inhibitors in sequence or in combination in AML clinical trials. -

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