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 and Boyi Gan ()
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Pranavi Koppula: The University of Texas MD Anderson Cancer Center
Guang Lei: The University of Texas MD Anderson Cancer Center
Yilei Zhang: The University of Texas MD Anderson Cancer Center
Yuelong Yan: The University of Texas MD Anderson Cancer Center
Chao Mao: The University of Texas MD Anderson Cancer Center
Lavanya Kondiparthi: Kadmon Corporation, LLC
Jiejun Shi: University of California
Xiaoguang Liu: The University of Texas MD Anderson Cancer Center
Amber Horbath: The University of Texas MD Anderson Cancer Center
Molina Das: The University of Texas MD Anderson Cancer Center
Wei Li: University of California
Masha V. Poyurovsky: Kadmon Corporation, LLC
Kellen Olszewski: Kadmon Corporation, LLC
Boyi Gan: The University of Texas MD Anderson Cancer Center

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-29905-1

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