The molecular basis of the anticancer effect of statins

Abstract

Statins, one of the most used class of cardiovascular drugs with the primary function of reducing blood cholesterol levels, exert their effect by inhibiting the enzyme HMG-CoA reductase, the key player in cholesterol biosynthesis. While the primary indication for statins is the prevention of cardiovascular diseases, there has been growing interest in their potential anticancer effects. However, the current evidence on these effects is largely based on epidemiological observations and preclinical research, not yet substantiated by knowledge of the mechanisms behind it. Here we show that statins have an anticancer effect as they exploit the principle of Synthetic Lethality, a concept in which the combination of two non-lethal genetic or molecular events results in cell death or impairment. When either of these events occurs alone, it is not lethal, but when they happen coupled, they create a lethal condition for the cell. In this work we report that statins emerged from a computational data analysis that we performed on approximately 37,000 synthetic lethality couples. We performed this analysis to select repurposable drugs that could target genes involved in Synthetic Lethality couples with metastatic genes. We validated our discoveryin vitroby drug tests performed on cell lines derived from cancers of the breast, ovary, and cervix. Our data-driven drug repurposing strategy allowed us to understand the molecular basis of the anticancer effect of statins, a discovery which can be directly translated into practical clinical applications in oncology.