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Genome-Wide CRISPR Screening Reveals That mTOR Inhibition Initiates Ferritinophagy and Ferroptosis in Head and Neck

Keiichi Koshizuka1,2, Xingyu Wu1, Kuniaki Sato1

  • 1Moores Cancer Center, University of California San Diego, San Diego, California.

Cancer Research
|June 6, 2025
PubMed

Insights

mTOR inhibitors induce cancer cell death through ferritinophagy, increasing iron and causing ferroptosis. This discovery offers new strategies for head and neck squamous cell carcinoma treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling

Background:

  • Persistent activation of the PI3K/mTOR pathway is common in cancer.
  • mTOR inhibitors (mTORi) show limited clinical efficacy despite promising preclinical data.

Purpose of the Study:

  • To understand the anti-tumor mechanisms of mTORi in head and neck squamous cell carcinoma (HNSCC).
  • To identify novel therapeutic strategies targeting the PI3K/mTOR pathway.

Main Methods:

  • Genome-wide CRISPR screening in HNSCC models.
  • Analysis of ferritinophagy, intracellular iron levels, and lipid peroxidation.
  • Investigating ferroptosis induction by mTORi.

Main Results:

  • mTORi treatment induces ferritinophagy, leading to increased intracellular iron.
  • Elevated iron levels promote lipid peroxidation and ferroptosis, causing cancer cell death.
  • This mechanism explains the anti-tumor activity of mTORi in HNSCC.

Conclusions:

  • mTOR inhibition triggers a cascade leading to ferroptosis in HNSCC.
  • This pathway provides a rationale for combining mTORi with drugs targeting ferroptosis.
  • Reveals potential for multimodal precision therapies in HNSCC and other cancers with PI3K/mTOR pathway activation.

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