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A targetable CoQ-FSP1 axis drives ferroptosis- and radiation-resistance in KEAP1 inactive lung cancers
Pranavi Koppula1,2, Guang Lei1, Yilei Zhang1
1Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
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.
Insights
Targeting ferroptosis in lung cancer is challenging. This study reveals the ubiquinone (CoQ)-FSP1 axis as a key driver of resistance in KEAP1 mutant lung cancers, offering a new therapeutic target.
Area of Science:
- Oncology
- Cell Death Mechanisms
- Molecular Biology
Background:
- Ferroptosis, a lipid peroxidation-driven cell death, is a promising cancer therapy target.
- KEAP1 mutations are common in lung cancers, leading to resistance against therapies like radiotherapy.
- Understanding ferroptosis regulation in specific cancer contexts is crucial for effective treatment.
Purpose of the Study:
- To investigate the mechanisms of ferroptosis resistance in KEAP1-mutant lung cancers.
- To identify novel therapeutic targets for KEAP1-mutant lung cancers.
- To explore the role of the ubiquinone (CoQ)-FSP1 axis in ferroptosis and radiation resistance.
Main Methods:
- Identification of ferroptosis suppressor protein 1 (FSP1) as a transcriptional target of NRF2.
- Analysis of the CoQ-FSP1 axis in KEAP1-deficient lung cancer cells.
- Pharmacological inhibition of the CoQ-FSP1 axis in vitro and in vivo models.
Main Results:
- FSP1 is a downstream target of the KEAP1-NRF2 pathway.
- The CoQ-FSP1 axis confers resistance to ferroptosis and radiation in KEAP1-deficient lung cancer.
- Inhibition of the CoQ-FSP1 axis sensitizes KEAP1-mutant lung cancer to radiation by inducing ferroptosis.
Conclusions:
- The CoQ-FSP1 axis is a critical mediator of resistance in KEAP1-mutant lung cancers.
- Targeting the CoQ-FSP1 axis represents a potential therapeutic strategy for KEAP1-mutant lung cancers.
- This study elucidates a novel mechanism of ferroptosis regulation and resistance in lung cancer.
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