Melanogenesis regulates susceptibility of melanoma cells to ferroptosis

Melanoma resistance to Braf and immune checkpoint inhibitors is a major clinical problem. One common mode of resistance is the treatment-driven dedifferentiation of melanoma cells. Recent reports suggested that melanoma dedifferentiation leads to an increase in cancer cell susceptibility to ferroptosis, a non-apoptotic programmed cell death pathway. This provides a unique opportunity to kill dedifferentiated melanoma cells by the process of ferroptosis. However, the mechanism of increased susceptibility to ferroptosis in dedifferentiated melanoma cells is not known. We found that melanogenesis (melanin synthesis) may explain why the state of differentiation of melanoma cells dictates their susceptibility to ferroptosis. Utilizing a tyrosinase deficient melanoma cell line and a pharmacologic modulation of melanogenesis, we determined that melanoma dedifferentiation downregulates eumelanin synthesis, producing a compensatory increase in pheomelanin. Based on our novel HPLC/MS-based analytical method of melanin precursors, we observed a biased utilization of eumelanin precursors and of cysteine-containing pheomelanin precursors by differentiated and dedifferentiated melanoma cells, respectively. Our findings suggest that an increased incorporation of cysteine into pheomelanin in the dedifferentiated melanoma decreases cellular glutathione required for the reduction of lipid peroxidation products. Therefore, we posit a mechanism whereby melanogenesis modulates melanoma susceptibility to ferroptosis by regulating intracellular glutathione levels. Targeting this mechanism presents a novel strategy to circumvent melanoma resistance to standard of care combination therapies.