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.

中文翻译：

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S645C 点突变抑制 EGFR 的降解以促进胶质母细胞瘤的进展。

背景 EGFR 的严格控制活性对于人体组织自我更新的稳态很重要。EGFR 细胞外结构域的突变是常见的，并且是 GBM 中致癌 EGFR 激活的一种新机制，并影响患者对小分子抑制剂的反应。方法构建稳定表达野生型EGFR和EGFR S645C突变体的胶质母细胞瘤细胞系。我们在体外和体内检测到细胞生长。我们评估了吉非替尼和奥希替尼在细胞中的抗肿瘤活性和有效性。结果在本研究中，我们鉴定了EGFR-S645C的致癌替代突变。该突变可促进胶质母细胞瘤在体外和体内的增殖和集落形成。机械地，EGFR S645C 突变可能会改变二聚 EGFR 内氢键的形成并抑制 EGFR 的降解以延长下游信号传导。该突变诱导了对吉非替尼的耐药性，但为奥希替尼的治疗提供了机会。结论 该研究表明了一种新的致癌突变，并建议对具有 EGFR S645C 突变的个体患者进行精确治疗。