Mevastatin can increase toxicity in primary AMLs exposed to standard therapeutic agents, but statin efficacy is not simply associated with ras hotspot mutations or overexpression

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase is a rate-limiting enzyme in the mevalonate biochemical pathway and HMG-CoA reductase inhibitors (statins) show toxicity for certain tumors, including acute myeloid leukemia (AML). This toxicity has been attributed to statin inhibition of Ras isoprenylation in tumors like AML where oncogenic ras mutations and/or overexpression are common. We show that mevastatin kills certain AML cell lines and is more toxic to a majority of primary AML cell samples than to myeloid cells in bone marrow (BM) samples from normal donors, and that mevastatin can produce more than additive kill with standard chemotherapeutics. Mevastatin reduces Ras membrane localization, but statin sensitivity in primary AML cells is not consistently associated with ras mutations nor with Ras overexpression, suggesting that another mevalonate pathway by-product(s) is the statin target in at least some AMLs.