作者
Mengmeng Niu,Jing Xu,Yang Liu,Yuhuang Li,Tao He,Liangping Ding,Yajun He,Yong Yi,Fengtian Li,Rongtian Guo,Ya Gao,Rui Li,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.