Sensitizing cancer cells to ferroptosis: a ‘radically’ different approach to tackle advanced and therapy-resistant cancer

One of the major challenges in the therapy of cancers is the ease with which tumors escape molecular targeted therapies. This is dramatically illustrated in case of malignant melanoma which emphasizes the need for better understanding of the mechanisms underlying acquired resistance. This is urgently required to develop rational novel strategies to either delay the onset of, or overcome cancer progression. Solid preliminary evidence from our team pinpoints altered lipid metabolism as one of central downstream pathways which mediates targeted therapy resistance in BRAF mutant melanoma. Our data indicates that in therapy-resistant cells de nevo lipogenesis is upregulated to protect melanoma cells by modulating membrane lipid saturation and redox balance. Further evidence shows that lipogenesis inhibition resensitizes melanoma to targeted therapy. The demonstrated increase in polyunsaturation of lipids compromises cell death through the lipid peroxidation. Therefore, the outstanding questions is whether activation of ferroptosis can be exploited to achieve desirable therapeutic ends.