eIF4E2 deficiency translationally unleashes WRN to sustain DNA repair-mediated chemoresistance
Xianrong Lin1, Rui Zhang1, Wenjun Tao1
1School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China.
Abstract:
Therapeutic resistance to DNA-damaging agents (DDAs) remains a primary obstacle in non-small cell lung cancer (NSCLC) treatment. Through multi-level analyses of clinical cohorts, cell lines, and derived resistant models, we identify eIF4E2 as a promising predictor of resistance to diverse DDAs. Using cisplatin as a model DDA, we find that eIF4E2 deficiency enhances DNA repair and promotes chemoresistance. Mechanistically, eIF4E2 represses translation of the DNA repair helicase WRN by recruiting the miRISC/CCR4-NOT complex to its 3'UTR via hsa-miR-130b-3p/301b-3p. Loss of eIF4E2 relieves WRN translation repression, potentiating DNA repair and attenuating DDA-induced DNA damage. Furthermore, combining the WRN inhibitor HRO761 with cisplatin enhances cytotoxicity in cisplatin-resistant cells. Collectively, these results establish that low eIF4E2 and high WRN levels predict chemoresistance, and that targeting WRN is a promising strategy to overcome cisplatin resistance in NSCLC.
Insights
Low eIF4E2 levels predict resistance to DNA-damaging agents in non-small cell lung cancer (NSCLC). Targeting WRN, a DNA repair protein, can overcome this chemoresistance.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Therapeutic resistance to DNA-damaging agents (DDAs) is a major challenge in non-small cell lung cancer (NSCLC) treatment.
- Identifying biomarkers and therapeutic targets is crucial for improving patient outcomes.
Purpose of the Study:
- To identify predictors of DDA resistance in NSCLC.
- To elucidate the molecular mechanisms underlying chemoresistance.
- To evaluate WRN inhibition as a strategy to overcome DDA resistance.
Main Methods:
- Multi-level analyses of clinical NSCLC cohorts, cell lines, and resistant models.
- Investigated the role of eIF4E2 in DDA response using cisplatin as a model agent.
- Examined the translational regulation of WRN by eIF4E2 via microRNA pathways.
- Assessed the efficacy of combining a WRN inhibitor (HRO761) with cisplatin in resistant cells.
Main Results:
- eIF4E2 was identified as a predictor of resistance to various DDAs.
- eIF4E2 deficiency enhanced DNA repair and promoted chemoresistance by relieving WRN translation repression.
- Loss of eIF4E2 led to increased WRN expression, potentiating DNA repair and reducing DDA-induced DNA damage.
- Combined treatment with HRO761 and cisplatin enhanced cytotoxicity in cisplatin-resistant NSCLC cells.
Conclusions:
- Low eIF4E2 and high WRN expression levels are associated with chemoresistance in NSCLC.
- Targeting WRN represents a promising therapeutic strategy to overcome DDA resistance in NSCLC.
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