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Metabolic Reprogramming Driven by IGF2BP3 Promotes Acquired Resistance to EGFR Inhibitors in Non-Small Cell Lung
Ziyou Lin1, Jingwei Li1, Jian Zhang2
1National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
A novel mechanism involving IGF2BP3 and COX6B2 drives acquired resistance to EGFR tyrosine kinase inhibitors (TKI) in lung cancer by reprogramming metabolism. Targeting this axis offers a strategy to overcome drug resistance.
Area of Science:
- Oncology
- Molecular Biology
- Metabolism
Background:
- Acquired resistance to EGFR tyrosine kinase inhibitors (TKI) is a major challenge in lung cancer treatment.
- Metabolic adaptation is a key feature of lung cancer and may contribute to drug resistance.
Purpose of the Study:
- To elucidate a novel mechanism of acquired resistance to EGFR-TKI in lung cancer.
- To investigate the role of IGF2BP3 and its downstream targets in mediating drug resistance.
Main Methods:
- Analysis of IGF2BP3 expression in TKI-resistant lung cancer patients.
- Investigating the interaction between IGF2BP3 and COX6B2 mRNA.
- Assessing the impact of the IGF2BP3-COX6B2 axis on oxidative phosphorylation (OXPHOS) and nicotinamide metabolism.
- Evaluating the efficacy of an OXPHOS inhibitor (IACS-010759) in preclinical models.
Main Results:
- IGF2BP3 was upregulated in TKI-resistant lung cancer and correlated with poor survival.
- IGF2BP3 binds to COX6B2 mRNA, increasing its stability and promoting OXPHOS.
- The IGF2BP3-COX6B2 axis influences nicotinamide metabolism, contributing to EGFR-TKI resistance.
- Inhibition of OXPHOS suppressed tumor growth in gefitinib-resistant models.
Conclusions:
- The IGF2BP3-COX6B2 axis drives acquired resistance to EGFR-TKI in lung cancer through metabolic reprogramming.
- Targeting OXPHOS presents a potential therapeutic strategy to overcome acquired resistance in lung cancer.
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