Sorafenib sensitizes melanoma cells to vemurafenib through ferroptosis

BRAF gene mutation causes melanoma patients to develop drug resistance after 8-9 months BRAF inhibitors treatment. Therefore, overcoming BRAF inhibitor resistance has important implications for improving patient survival. Sorafenib directly inhibits tumor cell proliferation by blocking the RAF/MEK/ERK-mediated cell signaling pathway. It remains unknown that whether the combination of sorafenib with vemurafenib could sensitize melanoma cells to vemurafenib, and the underlying mechanism needs to be clarified.Vemurafenib resistant melanoma cells A375/Vem and SK-Mel-28/Vem were established by exposing to a series of concentration of vemurafenib. Cell viability was measured when A375 and SK-Mel-28 cells treated with vemurafenib or combined with sorafenib. Meanwhile the levels of Iron, GSH, MDA and reactive oxygen species (ROS) were detected. Finally we examined that whether sorafenib sensitizes melanoma cells to vemurafenib through ferroptosis.We found that sorafenib sensitized melanoma cells to vemurafenib. Sorafenib treatment did not significantly alter the production of ROS and the content of iron, GSH and MDA in vemurafenib resistant cells, but cotreatment of sorafenib and vemurafenib dramatically upregulated ROS production, MDA and iron, but decreased GSH concentration. Interestingly, sorafenib strongly promoted vemurafenib-induced cell death, which was blocked by lipid peroxidation inhibitors ferrostatin-1 but not ZVAD-FMK or necrosulfonamid.Sorafenib sensitized melanoma cells to vemurafenib by increasing ROS production through ferroptosis. Our study reveals that the combination of sorafenib may provide a novel strategy of vemurafenib resistant melanoma therapy.