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

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