作者
Mengmeng Niu,Jing Xu,Yang Liu,Yuhuang Li,Tao He,Liangping Ding,Y. He,Yong Yi,Fengtian Li,Rongtian Guo,Ya Gao,Shunzhao Sui,Luping Li,Mengyuan Fu,Qingyong Hu,Yangkun Luo,Chunyan Zhang,Kewei Qin,Jianqiao Yi,Shuhan Yu,Jian Yang,Hu Chen,Liang Wang,Zhonghan Li,Biao Dong,Shiqian Qi,Liang Ouyang,Yujun Zhang,Yang Cao,Zhi‐Xiong Jim Xiao
摘要
Abnormal activation of epidermal growth factor receptor (EGFR) drives non-small cell lung cancer (NSCLC) development. EGFR mutations-mediated resistance to tyrosine-kinase inhibitors (TKIs) is a major hurdle for NSCLC treatment. Here, we show that F-box protein FBXL2 targets EGFR and EGFR TKI-resistant mutants for proteasome-mediated degradation, resulting in suppression of EGFR-driven NSCLC growth. Reduced FBXL2 expression is associated with poor clinical outcomes of NSCLC patients. Furthermore, we show that glucose-regulated protein 94 (Grp94) protects EGFR from degradation via blockage of FBXL2 binding to EGFR. Moreover, we have identified nebivolol, a clinically used small molecule inhibitor, that can upregulate FBXL2 expression to inhibit EGFR-driven NSCLC growth. Nebivolol in combination with osimertinib or Grp94-inhibitor-1 exhibits strong inhibitory effects on osimertinib-resistant NSCLC. Together, this study demonstrates that the FBXL2-Grp94-EGFR axis plays a critical role in NSCLC development and suggests that targeting FBXL2-Grp94 to destabilize EGFR may represent a putative therapeutic strategy for TKI-resistant NSCLC.