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

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 () and Zhi-Xiong Jim Xiao ()
Additional contact information
Mengmeng Niu: Ministry of Education, College of Life Sciences, Sichuan University
Jing Xu: Ministry of Education, College of Life Sciences, Sichuan University
Yang Liu: Ministry of Education, College of Life Sciences, Sichuan University
Yuhuang Li: Ministry of Education, College of Life Sciences, Sichuan University
Tao He: Ministry of Education, College of Life Sciences, Sichuan University
Liangping Ding: Ministry of Education, College of Life Sciences, Sichuan University
Yajun He: Ministry of Education, College of Life Sciences, Sichuan University
Yong Yi: Ministry of Education, College of Life Sciences, Sichuan University
Fengtian Li: Ministry of Education, College of Life Sciences, Sichuan University
Rongtian Guo: Ministry of Education, College of Life Sciences, Sichuan University
Ya Gao: Ministry of Education, College of Life Sciences, Sichuan University
Rui Li: Ministry of Education, College of Life Sciences, Sichuan University
Luping Li: Ministry of Education, College of Life Sciences, Sichuan University
Mengyuan Fu: Ministry of Education, College of Life Sciences, Sichuan University
Qingyong Hu: Ministry of Education, College of Life Sciences, Sichuan University
Yangkun Luo: Ministry of Education, College of Life Sciences, Sichuan University
Chunyan Zhang: Ministry of Education, College of Life Sciences, Sichuan University
Kewei Qin: Ministry of Education, College of Life Sciences, Sichuan University
Jianqiao Yi: Ministry of Education, College of Life Sciences, Sichuan University
Shuhan Yu: Ministry of Education, College of Life Sciences, Sichuan University
Jian Yang: Ministry of Education, College of Life Sciences, Sichuan University
Hu Chen: Ministry of Education, College of Life Sciences, Sichuan University
Liang Wang: Ministry of Education, College of Life Sciences, Sichuan University
Zhonghan Li: Ministry of Education, College of Life Sciences, Sichuan University
Biao Dong: State Key Laboratory of Biotherapy, West China Hospital, Sichuan University
Shiqian Qi: State Key Laboratory of Biotherapy, West China Hospital, Sichuan University
Liang Ouyang: State Key Laboratory of Biotherapy, West China Hospital, Sichuan University
Yujun Zhang: Ministry of Education, College of Life Sciences, Sichuan University
Yang Cao: Ministry of Education, College of Life Sciences, Sichuan University
Zhi-Xiong Jim Xiao: Ministry of Education, College of Life Sciences, Sichuan University

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-26222-x

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