Activation of RAS/MAPK pathway confers MCL-1 mediated acquired resistance to BCL-2 inhibitor venetoclax in acute myeloid leukemia
Qi Zhang, Bridget Riley‐Gillis, Lina Han, Yannan Jia, Alessia Lodi, Haijiao Zhang, Saravanan Ganesan, Rongqing Pan, Sergej Konoplev, Shannon Sweeney, Jeremy Ryan, Yulia Jitkova, Kenneth Dunner, Shaun Grosskurth, Priyanka Vijay, Sujana Ghosh, Charles Lu, Wencai Ma, Stephen E. Kurtz, Vivian Ruvolo, Helen Ma, Connie C. Weng, Cassandra L. Ramage, Natalia Baran, Ce Shi, Tianyu Cai, R. Eric Davis, Venkata Lokesh Battula, Yingchang Mi, Jing Wang, Courtney D. DiNardo, Michael Andreeff, Jeffery W. Tyner, Aaron D. Schimmer, Anthony Letai, Rose Ann Padua, Carlos E. Bueso‐Ramos, Stefano Tiziani, Joel D. Leverson, Relja Popovic, Marina Konopleva
Abstract
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.