| Literature DB >> 33217342 |
Shruti Bhatt1, Marissa S Pioso2, Elyse Anne Olesinski2, Binyam Yilma2, Jeremy A Ryan2, Thelma Mashaka2, Buon Leutz3, Sophia Adamia4, Haoling Zhu4, Yanan Kuang3, Abhishek Mogili3, Abner Louissaint4, Stephan R Bohl2, Annette S Kim5, Anita K Mehta6, Sneha Sanghavi7, Youzhen Wang7, Erick Morris7, Ensar Halilovic7, Cloud P Paweletz8, David M Weinstock2, Jacqueline S Garcia4, Anthony Letai9.
Abstract
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.Entities:
Keywords: BCL-2; BH3 mimetics; BH3 profiling; FLT-3; MCL-1; SMAC; leukemia; mitochondria; precision cancer medicine; venetoclax
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Year: 2020 PMID： 33217342 PMCID： PMC7988687 DOI： 10.1016/j.ccell.2020.10.010
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743