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A Novel MCL1 Inhibitor Combined with Venetoclax Rescues Venetoclax-Resistant Acute Myelogenous Leukemia. | LitMetric

AI Article Synopsis

  • The study focuses on the antiapoptotic BCL2 family proteins, especially MCL1, which is commonly upregulated in acute myeloblastic leukemia (AML) and contributes to resistance against the BCL2 inhibitor venetoclax.
  • Researchers introduced VU661013, a new selective MCL1 inhibitor that can trigger apoptosis in AML cells, including those resistant to venetoclax, and showed promising results when combined with venetoclax in animal models.
  • The findings support the strategy of using MCL1 and BCL2 inhibitors in sequence or combination for improved treatment effectiveness in AML, paving the way for future clinical trials.

Article Abstract

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 MCL1 inhibitor that destabilizes BIM/MCL1 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 accurately predicted cellular responses to selective inhibitors of MCL1 or BCL2 and showed benefit of the combination. Taken together, these data suggest a strategy of rationally using BCL2 and MCL1 inhibitors in sequence or in combination in AML clinical trials. SIGNIFICANCE: Targeting antiapoptotic proteins in AML is a key therapeutic strategy, and MCL1 is a critical antiapoptotic oncoprotein. Armed with novel MCL1 inhibitors 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...

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279595PMC
http://dx.doi.org/10.1158/2159-8290.CD-18-0140DOI Listing

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