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Targeting LRIG2 overcomes resistance to EGFR inhibitor in glioblastoma by modulating GAS6/AXL/SRC signaling

Cancer Gene Therapy volume 27, pages 878–897 (2020)Cite this article

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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.

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Fig. 1: LRIG2 is upregulated by EGFR inhibitor and confers resistance to EGFR inhibition in GBM.
Fig. 2: LRIG2 is expressed at higher levels in glioblastoma and positively correlated with AXL.
Fig. 3: LRIG2 promotes the activation of AXL/SRC signaling by enhancing the GAS6 secretion and protecting AXL from proteasome-mediated degradation.
Fig. 4: LRIG2 is involved in gefitinib resistance by modulating the GAS6/AXL/SRC signaling.
Fig. 5: Targeting LRIG2 sensitizes GBM cells to EGFR inhibition through influencing cell cycle progression and cell apoptosis.
Fig. 6: Inhibition of AXL activation abrogates LRIG2-mediated resistance to gefitinib in GBM cells.
Fig. 7: AXL inhibition abrogates LRIG2-mediated therapeutic resistance to EGFR inhibition in vivo.
Fig. 8: LRIG2 promotes resistance to gefitinib in GBM through modulating GAS6/AXL/SRC signaling in vivo.

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Acknowledgements

We thank all the staff who contributed their time and effort to this work and all patients who participated in the study. We also thank Anding Liu for the technical assistance.

Funding

This work was supported by the National Natural Science Foundation of China (no. 81472364 to BW, 81702480 to QX, and 81874086 to DG). The funding sources had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

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  1. These authors contributed equally: Minhai Dong, Qungen Xiao

Authors and Affiliations

  1. Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China

    Minhai Dong, Qungen Xiao, Jinyang Hu, Fangling Cheng, Po Zhang, Xiaopeng Li, Feng Mao, Yue He, Feng Wan, Ting Lei, Dongsheng Guo & Baofeng Wang

  2. Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China

    Weifeng Zong

  3. Department of Ultrasound, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China

    Qiaoying Tang

  4. Department of Histology and Embryology, College of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China

    Xingjiang Yu

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Dong, M., Xiao, Q., Hu, J. et al. Targeting LRIG2 overcomes resistance to EGFR inhibitor in glioblastoma by modulating GAS6/AXL/SRC signaling. Cancer Gene Ther 27, 878–897 (2020). https://doi.org/10.1038/s41417-020-0163-1

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