Oncogenic activation of PI3K-AKT-mTOR signaling suppresses ferroptosis via SREBP-mediated lipogenesis

Ferroptosis, a form of regulated necrosis driven by iron-dependent peroxidation of Phospholipids, is regulated by cellular metabolism, redox homeostasis, and various signaling pathways related to Cancer. In this study, we found that activating mutation of phosphatidylinositol 3-kinase (PI3K) or loss of Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) function, highly frequent events in human Cancer, confers Ferroptosis resistance in Cancer cells, and that inhibition of the PI3K-AKT-mTOR signaling axis sensitizes Cancer cells to Ferroptosis induction. Mechanistically, this resistance requires sustained activation of mTORC1 and the mechanistic target of rapamycin (mTOR)C1-dependent induction of sterol regulatory element-binding protein 1 (SREBP1), a central transcription factor regulating lipid metabolism. Furthermore, stearoyl-CoA desaturase-1 (SCD1), a transcriptional target of SREBP1, mediates the ferroptosis-suppressing activity of SREBP1 by producing monounsaturated fatty acids. Genetic or pharmacologic ablation of SREBP1 or SCD1 sensitized Ferroptosis in Cancer cells with PI3K-AKT-mTOR pathway mutation. Conversely, ectopic expression of SREPB1 or SCD1 restored Ferroptosis resistance in these cells, even when mTORC1 was inhibited. In xenograft mouse models for PI3K-mutated breast Cancer and PTEN-defective prostate Cancer, the combination of mTORC1 inhibition with Ferroptosis induction resulted in near-complete tumor regression. In conclusion, hyperactive mutation of PI3K-AKT-mTOR signaling protects Cancer cells from oxidative stress and ferroptotic death through SREBP1/SCD1-mediated lipogenesis, and combination of mTORC1 inhibition with Ferroptosis induction shows therapeutic promise in preclinical models.