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Reduced Mitochondrial Apoptotic Priming Drives Resistance to BH3 Mimetics in Acute Myeloid Leukemia

Bhatt, Shruti and Pioso, Marissa and Olesinski, Elyse and Yilma, Binyam and Leutz, Buon and Adamia, Sophia and Zhu, Holly and Yanan, Kuang and Mogili, Abhishek and Ryan, Jeremy and Wang, Youzhen and Morris, Erick and Halilovic, Ensar and Paweletz, Cloud P. and Weinstock, David M. and Garcia, Jacqueline S. and Letai, Anthony (2020) Reduced Mitochondrial Apoptotic Priming Drives Resistance to BH3 Mimetics in Acute Myeloid Leukemia. Cancer Cell, 38 (6). 872-890.e6. ISSN 18783686

Abstract

Bhatt et al. demonstrate that resistance to BCL-2 and MCL-1 antagonists emerges via selection for reduced mitochondrial apoptotic priming. Rapid measurements of drug-induced apoptotic signaling measured by dynamic BH3 profiling identify targeted agents with in vivo efficacy. BCL-2 and MCL-1 antagonist combinations overcome resistance to either single agent.

Acquired resistance to BH3 mimetic antagonists of BCL-2 and MCL-1 is an important clinical problem. Using acute myelogenous leukemia (AML) patient-derived xenograft (PDX) models of acquired resistance to BCL-2 (venetoclax) and MCL-1 (S63845) antagonists, we identify common principles of resistance and persistent vulnerabilities to overcome resistance. BH3 mimetic resistance is characterized by decreased mitochondrial apoptotic priming as measured by BH3 profiling, both in PDX models and human clinical samples, due to alterations in BCL-2 family proteins that vary among cases, but not to acquired mutations in leukemia genes. BCL-2 inhibition drives sequestered pro-apoptotic proteins to MCL-1 and vice versa, explaining why in vivo combinations of BCL-2 and MCL-1 antagonists are more effective when concurrent rather than sequential. Finally, drug-induced mitochondrial priming measured by dynamic BH3 profiling (DBP) identifies drugs that are persistently active in BH3 mimetic-resistant myeloblasts, including FLT-3 inhibitors and SMAC mimetics.

Item Type: Article
Keywords: BCL-2 BH3 mimetics BH3 profiling FLT-3 leukemia MCL-1 mitochondria precision cancer medicine SMAC venetoclax
Date Deposited: 25 Feb 2021 00:45
Last Modified: 25 Feb 2021 00:45
URI: https://oak.novartis.com/id/eprint/41565

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