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

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.

• Authors: Shruti Bhatt, Marissa S Pioso, Elyse Anne Olesinski, Binyam Yilma, Jeremy A Ryan, Thelma Mashaka, Buon Leutz, Sophia Adamia, Haoling Zhu, Yanan Kuang, Abhishek Mogili, Abner Louissaint Jr, Stephan R Bohl, Annette S Kim, Anita K Mehta, Sneha Sanghavi, Youzhen Wang, Erick Morris, Ensar Halilovic, Cloud P Paweletz, David M Weinstock, Jacqueline S Garcia, Anthony Letai
• Journal: Cancer cell (Cancer Cell) Vol. 38 Issue 6 Pg. 872-890.e6 (12 14 2020) ISSN: 1878-3686 [Electronic] United States
• PMID: 33217342 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Bax protein (53-86)
• Bridged Bicyclo Compounds, Heterocyclic
• Peptide Fragments
• Proto-Oncogene Proteins
• Pyrimidines
• S63845
• Sulfonamides
• Thiophenes
• venetoclax

Topics

• Animals
• Apoptosis
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Drug Resistance, Neoplasm
• Humans
• Leukemia, Myeloid, Acute (drug therapy, metabolism, pathology)
• Mice
• Mitochondria (drug effects, metabolism)
• Peptide Fragments (pharmacology)
• Proto-Oncogene Proteins (pharmacology)
• Pyrimidines (pharmacology)
• Signal Transduction
• Sulfonamides (pharmacology)
• Thiophenes (pharmacology)