文章：

靶向LRIG2通过调节GAS6/AXL/SRC信号克服胶质母细胞瘤对EGFR抑制剂的耐药性

Targeting LRIG2 overcomes resistance to EGFR inhibitor in glioblastoma by modulating GAS6/AXL/SRC signaling

原文发布日期：2020-01-28 

英文摘要：

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.

摘要翻译： 

表皮生长因子受体（EGFR）基因扩增与突变在胶质母细胞瘤（GBM）中发生频率最高。然而，包括吉非替尼在内的EGFR酪氨酸激酶抑制剂（TKIs）尚未展现出明确的临床获益，其潜在机制仍待深入探索。我们既往研究发现LRIG2在GBM中发挥促肿瘤作用，并作为多种致癌性受体酪氨酸激酶（RTKs）的调节因子。由此我们提出假设：LRIG2可能通过调控其他RTK信号通路介导对EGFR抑制剂的耐药性。本研究表明，在吉非替尼处理的GBM异种移植瘤或细胞系中，EGFR抑制剂可诱导LRIG2表达，其通过驱动细胞周期进程并抑制GBM细胞凋亡来促进对EGFR抑制的耐药性。机制上，LRIG2增加生长停滞特异性蛋白6（GAS6）的分泌，并通过阻止蛋白酶体介导的降解作用稳定AXL蛋白，从而增强吉非替尼诱导的AXL活化，进而重新激活被吉非替尼抑制的SRC信号。靶向LRIG2可显著提高GBM细胞对吉非替尼的敏感性，而抑制下游GAS6/AXL/SRC信号通路则能在体外和体内实验中消除LRIG2介导的吉非替尼耐药。综上所述，我们的研究揭示了EGFR抑制剂耐药的新机制，并为克服GBM中EGFR抑制剂耐药提供了潜在治疗策略。

原文链接：

Targeting LRIG2 overcomes resistance to EGFR inhibitor in glioblastoma by modulating GAS6/AXL/SRC signaling