Pitavastatin counteracts venetoclax resistance mechanisms in acute myeloid leukemia by depleting geranylgeranyl pyrophosphate.

ABSTRACT: The BCL2 inhibitor venetoclax has therapeutic activity in several hematological malignancies. In acute myeloid leukemia (AML), venetoclax combined with hypomethylating agents is the standard of care for patients unfit for intensive chemotherapy, but intrinsic and acquired resistance are common. Loss of p53 function is strongly associated with venetoclax resistance, and adding venetoclax to 5-azacitidine provides no overall survival benefit in TP53-mutant AML. Other frequent mechanisms of venetoclax resistance in AML include FLT3 mutations, MCL-1 upregulation, and altered mitochondrial metabolism. Unfortunately, it has been challenging to develop agents that target these mechanisms directly and combinatorially. Here we report that pitavastatin, an inhibitor of HMG-CoA-reductas

SUBMITTER: Buono R 

PROVIDER: S-EPMC12636571 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature