美国丹娜—法伯癌症研究所Anthony Letai研究组在研究中取得进展。他们的研究发现在急性髓样白血病患者中减少线粒体引起的细胞凋亡可导致对BH3模拟物的耐药性。相关论文在线发表在2020年11月19日出版的《癌细胞》杂志上。

使用对BCL-2（venetoclax）和MCL-1（S63845）拮抗剂具有抗性的急性骨髓性白血病（AML）患者来源的异种移植（PDX）模型，研究人员揭示了抗药性的普遍成因和克服该抗药性的持续性难题。BH3模拟物耐药性的特征在于，在PDX模型和人临床样品中，通过BH3谱系分析所检测到的线粒体凋亡触发减少，这是由于BCL-2家族蛋白的变化，这种变化因病例而异，但不属于白血病基因的获得性突变。

抑制BCL-2的作用将螯合的促凋亡蛋白驱逐到MCL-1，反之亦然，这解释了为什么当同时存在而不是顺序发生时，BCL-2和MCL-1拮抗剂的体内组合更有效。最后，通过BH3动态谱分析（DBP）药物诱导的线粒体凋亡可在对BH3模拟物产生抗性的成肌细胞中识别具有持续活性的药物，这包括FLT-3抑制剂和SMAC模拟物。

科学家介绍，解决对BCL-2和MCL-1拮抗剂BH3模拟物的获得性耐药是临床上面临的重要难题。

附：英文原文

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

Author: 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 J. Louissaint, 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

Issue&Volume: 2020-11-19

Abstract: Acquired resistance to BH3 mimetic antagonists of BCL-2 and MCL-1 is an importantclinical 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 overcomeresistance. BH3 mimetic resistance is characterized by decreased mitochondrial apoptoticpriming 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 acquiredmutations in leukemia genes. BCL-2 inhibition drives sequestered pro-apoptotic proteinsto MCL-1 and vice versa, explaining why in vivo combinations of BCL-2 and MCL-1 antagonists are more effective when concurrent ratherthan sequential. Finally, drug-induced mitochondrial priming measured by dynamic BH3profiling (DBP) identifies drugs that are persistently active in BH3 mimetic-resistantmyeloblasts, including FLT-3 inhibitors and SMAC mimetics.

DOI: 10.1016/j.ccell.2020.10.010

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30541-9