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

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.
Competing Interests: Declaration of Interests A.L. has consulted for and has received research support from AbbVie, Novartis, and AstraZeneca. He serves on the scientific advisory board of Flash Therapeutics, Dialectic Therapeutics, and Zentalis. J.S.G. received research funding from AbbVie, Genentech, Lilly, and Pfizer. She served on AbbVie advisory board. D.M.W. received research support from Novartis, Abbvie, AstraZeneca, Aileron, Daiichi-Sankyo, and Verastem. He is a founder and equity holder of Ajax Therapeutics and Travera. He serves on scientific advisory boards of Bantam Therapeutics, EDO Mundipharma, and Ajax Therapeutics.
(Copyright © 2020 Elsevier Inc. All rights reserved.)