ArticleCancer gene therapy2020
Targeting LRIG2 overcomes resistance to EGFR inhibitor in glioblastoma by modulating GAS6/AXL/SRC signaling.
Article in Cancer gene therapy, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 15 citations in OpenAlex.
- AXL is associated with STAT3 activation in breast cancer.Molecular and clinical oncology · 2026Article
- LRIG2 suppresses NK cell-induced GSDME-mediated pyroptosis via the LAMP1-STAT3 pathway in glioma.Journal for immunotherapy of cancer · 2026Article
- Natural and Synthetic Compounds, Swords for Glioblastoma Therapy: From Tumor to Its Microenvironment.International journal of molecular sciences · 2026Review
- Dysregulation of post-translational modifications in glioma: advances in pathological mechanisms and clinical targeting strategies.Journal of translational medicine · 2026Review
- Article
- Knockdown of Gas6 Exerts Anti-Esophageal Cancer Effects by Inhibiting the PI3K/AKT Pathway.Current issues in molecular biology · 2024Article
- Neurogenic Defects Occur inKidney international reports · 2023Article
- AXL in cancer: a modulator of drug resistance and therapeutic target.Journal of experimental & clinical cancer research : CR · 2023Review
- Establishment of two oxaliplatin-resistant gallbladder cancer cell lines and comprehensive analysis of dysregulated genes.Open medicine (Warsaw, Poland) · 2023Article
- LRIG2 promotes glioblastoma progression by modulating innate antitumor immunity through macrophage infiltration and polarization.Journal for immunotherapy of cancer · 2022Article
- Activation of STAT3 through combined SRC and EGFR signaling drives resistance to a mitotic kinesin inhibitor in glioblastoma.Cell reports · 2022Article
- Protein kinase CCell reports · 2021Article
- Article
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Authors and funding
15 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Epidermal growth factor receptor (EGFR) gene amplification and mutation occurs most frequently in glioblastoma (GBM). However, EGFR-tyrosine kinase inhibitors (TKIs), including gefitinib, have not yet shown clear clinical benefit and the underlying mechanisms remain largely unexplored. We previously demonstrated that LRIG2 plays a protumorigenic role and functions as a modulator of multiple oncogenic receptor tyrosine kinases (RTKs) in GBM. We therefore hypothesized that LRIG2 might mediate the resistance to EGFR inhibitor through modulating other RTK signaling. In this study, we report that LRIG2 is induced by EGFR inhibitor in gefitinib-treated GBM xenografts or cell lines and promotes resistance to EGFR inhibition by driving cell cycle progression and inhibiting apoptosis in GBM cells. Mechanistically, LRIG2 increases the secretion of growth-arrest specific 6 (GAS6) and stabilizes AXL by preventing its proteasome-mediated degradation, leading to enhancement of the gefitinib-induced activation of AXL and then reactivation of the gefitinib-inhibited SRC. Targeting LRIG2 significantly sensitizes the GBM cells to gefitinib, and inhibition of the downstream GAS6/AXL/SRC signaling abrogates LRIG2-mediated gefitinib resistance in vitro and in vivo. Collectively, our findings uncover a novel mechanism in resistance to EGFR inhibition and provide a potential therapeutic strategy to overcome resistance to EGFR inhibition in GBM.
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