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

Qi ZhangBridget Riley-GillisLina HanYannan JiaAlessia LodiHaijiao ZhangSaravanan GanesanRongqing PanSergej N KonoplevShannon R SweeneyJeremy Adam RyanYulia JitkovaKenneth DunnerShaun E GrosskurthPriyanka VijaySujana GhoshCharles LuWencai MaStephen KurtzVivian R RuvoloHelen MaConnie C WengCassandra L RamageNatalia BaranCe ShiTianyu CaiRichard Eric DavisVenkata Lokesh BattulaYingchang MiJing WangCourtney D DiNardoMichael AndreeffJeffery W TynerAaron SchimmerAnthony G LetaiRose Ann PaduaCarlos E Bueso-RamosStefano TizianiJoel LeversonRelja PopovicMarina Konopleva
Published in: Signal transduction and targeted therapy (2022)
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.
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