Macrocyclic Lactones Block Melanoma Growth, Metastases Development and Potentiate Activity of Anti–BRAF V600 Inhibitors

Abstract

IntroductionMelanoma is the most aggressive form of skin cancer. Targeted antimelanoma therapies such as BRAF V600 inhibitors have shown spectacular results. However, these therapies are restricted to BRAF V600 mutated melanoma and display both adverse effects and resistance outbreaks. MethodsA high-content screening campaign identified compounds that displayed antimelanoma activities that can potentiate anti–BRAF V600 inhibitors. We identified ivermectin, a US Food and Drug Administration (FDA)-approved macrocyclic lactone widely used as an anthelmintic and insecticidal agent. ResultsMacrocyclic lactones possess in vitro cytotoxicity against either BRAF wild type (wt) or BRAF V600 mutated melanoma cells lines. Daily intraperitoneal injections of ivermectin strongly reduce pulmonary metastasis implantation in vivo in murine and melanoma models. Interestingly, these macrocyclic lactones are also able to trigger vemurafenib-dependent cytotoxicity in vitro in BRAF-wt melanoma cells, although vemurafenib action was thought to be restricted to melanoma bearing the BRAF V600 mutation. These macrocyclic lactones are also able to increase the in vitro antimelanoma activity of another BRAF V600 clinical inhibitor, dabrafenib. Serine/threonine p21-activated protein kinase 1 (PAK1) is the key target of ivermectin responsible for its antimelanoma activity. ConclusionIvermectin is a promising agent that could strongly increase melanoma therapy efficiency because it is cytotoxic for BRAF-wt and BRAF mutated melanomas and because it increases the efficiency of antimutated BRAF inhibitors independent of the BRAF status of tumors. Because ivermectin is FDA approved and a study of ivermectin would be able to include all patients in the same protocol, this combination treatment should be next investigated in clinical studies.