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.
Zhang Q, Riley-Gillis B, Han L, Jia Y, Lodi A, Zhang H, Ganesan S, Pan R, Konoplev SN, Sweeney SR, Ryan JA, Jitkova Y, Dunner K Jr, Grosskurth SE, Vijay P, Ghosh S, Lu C, Ma W, Kurtz S, Ruvolo VR, Ma H, Weng CC, Ramage CL, Baran N, Shi C, Cai T, Davis RE, Battula VL, Mi Y, Wang J, DiNardo CD, Andreeff M, Tyner JW, Schimmer A, Letai A, Padua RA, Bueso-Ramos CE, Tiziani S, Leverson J, Popovic R, Konopleva M.
