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.

获得性对 BCL-2 和 MCL-1 的 BH3 模拟拮抗剂的耐药性是一个重要的临床问题。使用对 BCL-2 (venetoclax) 和 MCL-1 (S63845) 拮抗剂获得性耐药的急性髓性白血病 (AML) 患者衍生异种移植 (PDX) 模型，我们确定了耐药性的共同原则和克服耐药性的持续脆弱性。在 PDX 模型和人类临床样本中，BH3 模拟物抗性的特征在于通过 BH3 分析测量的线粒体凋亡启动减少，这是由于 BCL-2 家族蛋白的改变在不同病例中有所不同，但不是白血病基因的获得性突变。BCL-2 抑制将隔离的促凋亡蛋白驱动至 MCL-1，反之亦然，这解释了为什么在体内BCL-2 和 MCL-1 拮抗剂的组合在同时使用时比连续使用时更有效。最后，通过动态 BH3 分析 (DBP) 测量的药物诱导的线粒体启动可识别在 BH3 模拟耐药成髓细胞中持续活跃的药物，包括 FLT-3 抑制剂和 SMAC 模拟。