AUTHOR=Huang Wenda , Zou Ling , Hao Zhaonian , Wang Baofeng , Mao Feng , Duan Qiuhong , Guo Dongsheng TITLE=S645C Point Mutation Suppresses Degradation of EGFR to Promote Progression of Glioblastoma JOURNAL=Frontiers in Oncology VOLUME=12 YEAR=2022 URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.904383 DOI=10.3389/fonc.2022.904383 ISSN=2234-943X 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.