A targetable CoQ-FSP1 axis drives ferroptosis- and radiation-resistance in KEAP1 inactive lung cancers

Pranavi Koppula, Guang Lei, Yilei Zhang, Yuelong Yan, Chao Mao, Lavanya Kondiparthi, Jiejun Shi, Xiaoguang Liu, Amber Horbath, Molina Das, Wei Li, Masha V. Poyurovsky, Kellen Olszewski, Boyi Gan

Research output: Contribution to journalArticlepeer-review

174 Scopus citations

Abstract

Targeting ferroptosis, a unique cell death modality triggered by unrestricted lipid peroxidation, in cancer therapy is hindered by our incomplete understanding of ferroptosis mechanisms under specific cancer genetic contexts. KEAP1 (kelch-like ECH associated protein 1) is frequently mutated or inactivated in lung cancers, and KEAP1 mutant lung cancers are refractory to most therapies, including radiotherapy. In this study, we identify ferroptosis suppressor protein 1 (FSP1, also known as AIFM2) as a transcriptional target of nuclear factor erythroid 2-related factor 2 (NRF2) and reveal that the ubiquinone (CoQ)-FSP1 axis mediates ferroptosis- and radiation- resistance in KEAP1 deficient lung cancer cells. We further show that pharmacological inhibition of the CoQ-FSP1 axis sensitizes KEAP1 deficient lung cancer cells or patient-derived xenograft tumors to radiation through inducing ferroptosis. Together, our study identifies CoQ-FSP1 as a key downstream effector of KEAP1-NRF2 pathway and as a potential therapeutic target for treating KEAP1 mutant lung cancers.

Original languageEnglish (US)
Article number2206
JournalNature communications
Volume13
Issue number1
DOIs
StatePublished - Dec 2022
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General
  • General Physics and Astronomy

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