International Session 15　　Cancer Chemotherapy

Genomic alterations converging in persistent activation of the PI3K/mTOR pathway represent one of the most frequently altered signaling circuitries in cancer.This abnormal activation is observed in about 80 of Head and neck squamous cell carcinoma(HNSCC)cases.This overreliance on PI3K/mTOR signaling for tumor growth may expose a cancer vulnerability that can be exploited therapeutically.However, the clinical efficacy of mTOR inhibitors(mTORi)for HNSCC treatment has been limited.Here, we took advantage of a whole-genome CRISPR screening approach to search for mechanisms making cells resistant to mTORi, and autophagy and ferrroptosis was identified.Ferroptosis is iron-dependent regulated cell death process caused by the peroxidation of polyunsaturated fatty acids.Indeed, mTORi was demonstrated to induce ferroptosis in HNSCC cells, and inhibition of ferroptosis reduced the effect of mTORi.This study provides direct and detailed mechanisms linking mTORi-triggered autophagy and ferroptosis.Our studies uncovered how mTORi act in HNSCC, thereby revealing new multimodal precision therapies for HNSCC and many human malignancies displaying overactive PI3K/mTOR signaling.