Preclinical Potentiators of Statin-induced Anticancer Effects

Statins have been used for decades in the treatment of hypercholesterolemic patients to decrease the incidence of adverse cardiovascular events. Statins target the rate-limiting enzyme of the mevalonate (MVA) pathway, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR). Statin-mediated HMGCR inhibition in hepatocytes leads to depletion of MVA derived sterols, including cholesterol, and a subsequent uptake of low-density lipoprotein (LDL) cholesterol from the plasma. Aside from the intended cholesterol-lowering properties, statins exert many pleiotropic effects including anti-tumour activity. The well characterized pharmacokinetic profiles, safety and the fact that many statins are off patent has ensured their prompt entry into clinic for evaluation of anti-cancer efficacy. We hypothesize that the therapeutic window of statins can be increased through (i) the use of a pharmacological screen to identify compound/s that synergize with statins to induce tumour-specific apoptosis and (ii) the use of a genome-wide small hairpin ribonucleic acid (shRNA) screen to identify novel pathways/targets whose knockdown enhances the vulnerability of tumour cells to statin-inhibition. Firstly we carried out a screen in a multiple myeloma (MM) cell line where we combined atorvastatin with other off-patent FDA approved drugs. We identified dipyridamole, a commonly used anti-platelet agent as synergizing with and potentiating statin-induced apoptosis in a variety of MM and acute meylogenous leukemia (AML) cell lines and primary patient samples. The efficacy of the combination was demonstrated in vivo. Secondly, through genome-wide shRNA screen, we identified several putative targets whose knockdown potentiated statin induced anti-cancer effects in the A549 lung cancer cell line. Amongst the most promising hits, sterol regulatory element binding transcription factor 2 (SREBF2) was validated in lung and breast cancer cell lines. The knockdown of SREBF2 was found to dramatically potentiate statin-induced apoptosis and block the upregulation sterol-responsive gene targets. Taken together, this research has uncovered a novel combination of clinically translatable drugs with strong preclinical efficacy in hematological malignancies. Furthermore we have identified several novel validated targets that sensitize the MVA pathway to statin-induced apoptosis.Ph