ERK1/2 Inhibition Overcomes Resistance to Venetoclax in AML By Inhibiting Drp1 Dependent Mitochondrial Fission

Acute myeloid leukemia (AML) is a fatal hematological malignancy for most patients, and (MAPK) cascade is activated in 70%-80% of AML patients owing to activating/inactivating mutations in RAS and upstream proteins. Mutations in the RAS pathway are associated with secondary clinical resistance to venetoclax (ABT199) and hypomethylating agents. We found that ERK1/2 inhibition leads to increased mitochondrial length as well as overcomes resistance to venetoclax. To identify the factors that contribute to synergy and overcome resistance, we perfomed transcriptome profiling of AML cells treated with ABT199, ERK1/2 inhibitor or the combination treatment.Transcriptome analysis revealed downregulation of DRP1, a fission GTPase and a direct downstream target of ERK1/2, in response to ERKi +/-ABT199.