Oncogenic RTKs sensitize cancer cells to ferroptosis via c-Myc mediated upregulation of ACSL4.

Alteration or abnormal activation of RTKs have been recurrently observed and recognized as an important driving factor in the progression of many human cancers. Ferroptosis, an iron-dependent form of regulated necrosis triggered by the accumulation of lethal lipid peroxides on cell membranes, has been implicated in various tumor types. Here we reported that oncogenic RTKs/RAS/RAF/c-Myc axis promotes cancer cells to ferroptosis. Mechanistically, c-Myc binds to the promoter region of ACSL4 and promotes the expression of ACSL4, thereby sensitizes cells to ferroptosis. We further showed that RTKs/RAS/RAF promote ferroptosis by upregulating c-Myc mediated expression of ACSL4 in cancer cells. Notably, overexpression of RTKs enhances the vulnerability of melanoma to the ferroptosis inducer in mouse xenograft model. These findings may provide an attractive intervention strategy to target cancers with oncogenic activation of RTKs via a ferroptosis-inducing approach.