2. Academic Validation
  3. An alternative EGFR activation by patient-derived R252C mutation promotes cancer progression

An alternative EGFR activation by patient-derived R252C mutation promotes cancer progression

  • Nat Commun. 2026 Jan 21;17(1):1902. doi: 10.1038/s41467-026-68699-4.
Yajuan Zhang # 1 2,  Qizhen Fei # 3,  Yan Li # 4,  Siyao Wang # 2,  Tong Rong 1,  Xueyuan Wu 5,  Hong Gao 2,  Chen Chen 6 7,  Dong Gao 2,  Yun Zhao 2,  Guohui Li 4,  Huiying Chu 8,  Wenfeng Li 9,  Weiwei Yang 10 11 12
Affiliations

Affiliations

  • 1 Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 Key Laboratory of Multi-cell Systems, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 3 Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 4 Interdisciplinary Research Center for Biology and Chemistry, Liaoning Normal University, Dalian, Liaoning, China.
  • 5 Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 6 Department of Radiation Oncology, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 7 Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 8 Interdisciplinary Research Center for Biology and Chemistry, Liaoning Normal University, Dalian, Liaoning, China. [email protected].
  • 9 Department of Radiation Oncology, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China. [email protected].
  • 10 Key Laboratory of Multi-cell Systems, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 11 Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang, China. [email protected].
  • 12 Shanghai Academy of Natural Sciences (SANS), Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 41565660 DOI: 10.1038/s41467-026-68699-4
Abstract

Mutations in the extracellular or intracellular domains of epidermal growth factor receptor (EGFR) are implicated in the development of various cancers. While the intracellular mutations of EGFR have been extensively studied, the function of extracellular mutations remains poorly understood. In this study, we identify an EGFR mutant (EGFR R252C) in a patient with multifocal lung Cancer and glioma, in which arginine (R) 252 is mutated to cysteine (C) in the EGFR extracellular domain. This mutation promotes C252-C252 disulfide-mediated EGFR dimerization and induces a conformational change of EGFR, leading to absent autophosphorylation and enhanced direct interaction between EGFR and extracellular signal-regulated protein kinase 1/2 (ERK1/2). Importantly, EGFR directly phosphorylates ERK1/2 at threonine (T) 202 / tyrosine (Y) 204 and activates ERK1/2, thereby promoting tumor cell proliferation and tumor growth in vivo. Afatinib, a second-generation EGFR tyrosine kinase inhibitor, effectively suppresses primary tumor growth and extends progression-free survival in the patient with multifocal lung Cancer and glioma driven by EGFR R252C. Our finding elucidates the activation mechanism of this extracellular EGFR mutation and demonstrates the efficacy of afatinib in treating lung Cancer or glioma patients with this variant.

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