FBXL2 counteracts Grp94 to destabilize EGFR and inhibit EGFR-driven NSCLC growth

• DOI: 10.1038/s41467-021-26222-x
• Publication Date: 2021-10-11T10:09:40Z
• Authors: 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
• Keywords: Osimertinib; EGFR Inhibitors; Growth inhibition

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 and TKI-resistant mutants proteasome-mediated degradation, resulting in suppression EGFR-driven growth. Reduced expression associated with poor clinical outcomes patients. Furthermore, glucose-regulated 94 (Grp94) protects from degradation via blockage binding EGFR. Moreover, have identified nebivolol, clinically used small molecule inhibitor, can upregulate inhibit Nebivolol combination osimertinib or Grp94-inhibitor-1 exhibits strong inhibitory effects on osimertinib-resistant NSCLC. Together, this study demonstrates the FBXL2-Grp94-EGFR axis plays critical role development suggests targeting FBXL2-Grp94 destabilize may represent putative therapeutic strategy