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

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 resis...

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Bibliographic Details
Published in:	Cancer discovery 2018-12, Vol.8 (12), p.1566-1581
Main Authors:	Ramsey, Haley E, Fischer, Melissa A, Lee, Taekyu, Gorska, Agnieszka E, Arrate, Maria Pia, Fuller, Londa, Boyd, Kelli L, Strickland, Stephen A, Sensintaffar, John, Hogdal, Leah J, Ayers, Gregory D, Olejniczak, Edward T, Fesik, Stephen W, Savona, Michael R
Format:	Article
Language:	eng
Subjects:	Acute Disease Animals Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Apoptosis - drug effects Bridged Bicyclo Compounds, Heterocyclic - pharmacology Cell Line, Tumor Drug Resistance, Neoplasm - drug effects Drug Synergism HL-60 Cells Humans Indoles - chemistry Indoles - pharmacology K562 Cells Leukemia, Myeloid - drug therapy Leukemia, Myeloid - metabolism Mice, Inbred NOD Mice, Knockout Mice, SCID Myeloid Cell Leukemia Sequence 1 Protein - antagonists & inhibitors Myeloid Cell Leukemia Sequence 1 Protein - metabolism Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors Proto-Oncogene Proteins c-bcl-2 - metabolism Pyrazines - chemistry Pyrazines - pharmacology Pyrazoles - chemistry Pyrazoles - pharmacology Sulfonamides - pharmacology THP-1 Cells U937 Cells Xenograft Model Antitumor Assays
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Summary:	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. . .
ISSN:	2159-8274 2159-8290