Development of a Cocktail Therapy against Human Malignant Melanoma by Combining Autophagy Inhibitors and Vemurafenib

Abstract

Metastatic melanoma, a malignancy originating from pigment-producing melanocytes, is the most aggressive form of skin cancer. Most patients with metastasized melanoma harbor the activating mutation gene, BRAF V600E. Vemurafenib (PLX4032), a BRAF inhibitor (BRAFi), develops drug resistance in the patients. Autophagy is a self-salvaging mechanism for cells to deal with different stresses and promotes cancer cell survival and growth. However, the role autophagy contributes to resistance to anti-tumor drugs is not well studied. In this research, we determine the effects of autophagy inhibitors, as well as a combination of autophagy inhibitors and Vemurafenib, on cell viability and cell migration. Autophagy inhibitors significantly reduced cell viability and inhibited cell migration of human malignant melanoma cells and displayed an additive cytotoxicity with PLX4032 in both Vemurafenib sensitive and resistant melanoma cells. Moreover, autophagy inhibitors alone, or combined with Vemurafenib, induced apoptosis in both Vemurafenib sensitive and resistant melanoma cells. We further examined the signaling pathways that autophagy inhibitors may employ to exert cytotoxic effect and overcome BRAFi resistance. Autophagy inhibitors alone activated Erk and worked synergistically with BRAFi to inhibit autophagy by reducing the expression of Atg12. In conclusion, our results suggest that a combination of autophagy inhibitors and BRAF would be a potential therapeutic strategy to treat melanoma and to overcome the drug resistance in the melanoma cells.