FBXL2 Counteracts Grp94 to Destabilize EGFR and Inhibit EGFR-driven NSCLC Growth

Overview

Journal Nat Commun

Specialty Biology

Date 2021 Oct 12

PMID 34635651

Citations 24

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

Affiliations

Soon will be listed here.

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.

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