S645C Point Mutation Suppresses Degradation of EGFR to Promote Progression of Glioblastoma

Wenda Huang; Ling Zou; Zhaonian Hao; Baofeng Wang; Feng Mao; Qiuhong Duan; Dongsheng Guo

doi:10.3389/fonc.2022.904383

S645C Point Mutation Suppresses Degradation of EGFR to Promote Progression of Glioblastoma

Front Oncol. 2022 Jun 23:12:904383. doi: 10.3389/fonc.2022.904383. eCollection 2022.

Authors

Wenda Huang¹, Ling Zou², Zhaonian Hao³, Baofeng Wang¹, Feng Mao¹, Qiuhong Duan², Dongsheng Guo¹

Affiliations

¹ Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
² Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
³ Department of Neurosurgery, Beijing TianTan Hospital, Capital Medical University, Beijing, China.

Abstract

Background: The tightly controlled activity of EGFR is important for the homeostasis of self-renewal of human tissue. Mutations in the extracellular domain of EGFR are frequent and function as a novel mechanism for oncogenic EGFR activation in GBM, and impact the response of patients to small-molecule inhibitors.

Methods: We constructed glioblastoma cell lines stably expressing wild-type EGFR and the mutant of EGFR S645C. We detected cell growth in vitro and in vivo. We evaluated the anti-tumor activity and effectiveness of gefitinib and osimertinib in cells.

Results: In the present study, we identified an oncogenic substituted mutation of EGFR-S645C. The mutation can promote the proliferation and colony formation of glioblastoma in vitro and in vivo. Mechanistically, the EGFR S645C mutation potentially changes the formation of hydrogen bonds within dimerized EGFR and inhibits the degradation of EGFR to prolong downstream signaling. The mutation induces resistance to gefitinib but presents an opportunity for osimertinib treatment.

Conclusion: The study indicated a novel oncogenic mutation and advises on the precise treatment of individual patients with the EGFR S645C mutation.

Keywords: EGFR; EGFR degradation; S645C point mutation; glioblastoma; individualized treatment; targeted therapy.