Targeting LRIG2 overcomes resistance to EGFR inhibitor in glioblastoma by modulating GAS6/AXL/SRC signaling
Authors: Ting Lei
Xingjiang Yu
Qungen Xiao
Qiaoying Tang
Dongsheng Guo
Fangling Cheng
Minhai Dong
Xiaopeng Li
Weifeng Zong
Po Zhang
Yue He
Feng Wan
Feng Mao
Jinyang Hu
Baofeng Wang
Journal: Cancer Gene Therapy (2020)
Discipline: CLINICAL MEDICINE
Keywords: EGFR; LRIG2; resistance; gefitinib; GBM
Affiliations: Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China., Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China., Department of Ultrasound, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China., Department of Histology and Embryology, College of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China., Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China. .

Abstract:  Epidermal growth factor receptor (EGFR) gene amplification and mutation occurs most frequently in glioblastoma (GBM). However, EGFR-tyrosine kinase inhibitors (TKIs), including gefitinib, have not yet shown clear clinical benefit and the underlying mechanisms remain largely unexplored. We previously demonstrated that LRIG2 plays a protumorigenic role and functions as a modulator of multiple oncogenic receptor tyrosine kinases (RTKs) in GBM. We therefore hypothesized that LRIG2 might mediate the resistance to EGFR inhibitor through modulating other RTK signaling. In this study, we report that LRIG2 is induced by EGFR inhibitor in gefitinib-treated GBM xenografts or cell lines and promotes resistance to EGFR inhibition by driving cell cycle progression and inhibiting apoptosis in GBM cells. Mechanistically, LRIG2 increases the secretion of growth-arrest specific 6 (GAS6) and stabilizes AXL by preventing its proteasome-mediated degradation, leading to enhancement of the gefitinib-induced activation of AXL and then reactivation of the gefitinib-inhibited SRC. Targeting LRIG2 significantly sensitizes the GBM cells to gefitinib, and inhibition of the downstream GAS6/AXL/SRC signaling abrogates LRIG2-mediated gefitinib resistance in vitro and in vivo. Collectively, our findings uncover a novel mechanism in resistance to EGFR inhibition and provide a potential therapeutic strategy to overcome resistance to EGFR inhibition in GBM. 

Retracted: No

PubPeer comments:
 Figure 8B contains two duplicate panels, though one has been rotated and the field of view is slightly different. Do the authors have any idea as to what happened here?  , 
 Dear Capillacea, Thank you very much for pointing out our mistake. After checking with the first author and carefully going through the original data, we realized that we used the wrong picture. We already contacted the journal editorial department and sent the original data for the correction. Nevertheless, we fully trust the validity of the original data, and the misuse of the image will not affect the main conclusion. We sincerely apologize for our carelessness in the original submission. Sincerely, Wang Baofeng ,