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

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.