789 Inhibition of isoprenylation synergizes with MAPK blockade to prevent growth in treatment-resistant melanoma

While originally approved for treatment of hypercholesterolemia, HMG-CoA reductase inhibitors, or statins, have also been postulated to have anti-cancer properties. Nevertheless, significant concern over their toxicity at required doses has limited their evaluation in the past. We demonstrate marked potentiation of statin-induced growth inhibition in BRAF-mutant melanoma, as well as NRAS-mutant melanoma in combination with small molecule MAPK inhibitors. We also present evidence that this effect is mediated by impaired production of isoprenoid farnesyl and geranylgeranyl groups: products of the mevalonate pathway, with downstream effects on both PI3K/AKT and Hippo signaling. Mouse studies of dual therapy with statins and BRAF inhibitors in the setting of vemurafenib-resistant BRAF-mutant melanoma provide additional in vivo evidence of efficacy, supporting a possible role for trials of statin and MAPK inhibitor combination therapy in human cancer patients.