A Novel MCL1 Inhibitor Combined with Venetoclax Rescues Venetoclax-Resistant Acute Myelogenous Leukemia
2018
Suppression of apoptosis by expression of antiapoptotic BCL2 family members is a hallmark of
acute myeloblastic leukemia(AML). Induced myeloid leukemia cell differentiation protein (
MCL1), an antiapoptotic BCL2 family member, is commonly upregulated in AML cells and is often a primary mode of resistance to treatment with the BCL2 inhibitor
venetoclax. Here, we describe VU661013, a novel, potent, selective
MCL1inhibitor that destabilizes BIM/
MCL1association, leads to apoptosis in AML, and is active in
venetoclax-resistant cells and patient-derived xenografts. In addition, VU661013 was safely combined with
venetoclaxfor 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
MCL1or BCL2 and showed benefit of the combination. Taken together, these data suggest a strategy of rationally using BCL2 and
MCL1inhibitors in sequence or in combination in AML clinical trials. Significance: Targeting antiapoptotic proteins in AML is a key therapeutic strategy, and
MCL1is a critical antiapoptotic oncoprotein. Armed with novel
MCL1inhibitors and the potent BCL2 inhibitor
venetoclax, it may be possible to selectively induce apoptosis by combining or thoughtfully sequencing these inhibitors based on a rational evaluation of AML. See related commentary by Leber et al., p. 1511 . This article is highlighted in the In This Issue feature, p. 1494
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