Activation of RAS/MAPK pathway confers MCL-1 mediated acquired resistance to BCL-2 inhibitor venetoclax in acute myeloid leukemia

作者：Zhang, Qi; Riley-Gillis, Bridget; Han, Lina; Jia, Yanan; Lodi, Alessia; Zhang, Haijiao; Ganesan, Saravanan; Pan, Rongqing; Konoplev, Sergej N.; Sweeney, Shannon R.; Ryan, Jeremy A.; Jitkova, Yulia; Dunner, Kenneth, Jr.; Grosskurth, Shaun E.; Vijay, Priyanka; Ghosh, Sujana; Lu, Charles; Ma, Wencai; Kurtz, Stephen; Ruvolo, Vivian R.; Ma, Helen; Weng, Connie C.; Ramage, Cassandra L.; Baran, Natalia; Shi, Ce; Cai, Tianyu; Davis, Richard Eric; Battula, Venkata L.; Mi, Yingchang; Wang, Jing

来源：Signal Transduction and Targeted Therapy, 2022, 7(1): 51.

DOI：10.1038/s41392-021-00870-3

• MITOCHONDRIAL FUSION
• CELL-DEATH
• ABT-737
• MECHANISMS
• EFFICACY
• OPA1

Despite high initial response rates, acute myeloid leukemia (AML) treated with the BCL-2-selective inhibitor venetoclax (VEN) alone or in combinations commonly acquires resistance. We performed gene/protein expression, metabolomic and methylation analyses of isogenic AML cell lines sensitive or resistant to VEN, and identified the activation of RAS/MAPK pathway, leading to increased stability and higher levels of MCL-1 protein, as a major acquired mechanism of VEN resistance. MCL-1 sustained survival and maintained mitochondrial respiration in VEN-RE cells, which had impaired electron transport chain (ETC) complex II activity, and MCL-1 silencing or pharmacologic inhibition restored VEN sensitivity. In support of the importance of RAS/MAPK activation, we found by single-cell DNA sequencing rapid clonal selection of RAS-mutated clones in AML patients treated with VEN-containing regimens. In summary, these findings establish RAS/MAPK/MCL-1 and mitochondrial fitness as key survival mechanisms of VEN-RE AML and provide the rationale for combinatorial strategies effectively targeting these pathways.

• 单位
  中国医学科学院; 哈尔滨医科大学; 中国医学科学院北京协和医院; 1