The epidermal growth factor receptor (EGFR) is a key oncogenic driver gene in various malignant tumors, including lung cancer. A series of targeted drugs have been successfully applied in clinical practice for its classic mutation types (such as the L858R point mutation and exon 19 deletion).
However, the molecular mechanisms underlying the oncogenicity of some rare EGFR mutation subtypes carried by certain patients are not fully elucidated, leading to suboptimal clinical treatment responses. Therefore, identifying and elucidating the pathogenic mechanisms of rare EGFR mutations is one of the critical challenges to overcome in the field of tumor precision medicine.
In a study published in Nature Communications, the team led by Prof. YANG Weiwei from the Center for Excellence in Molecular Cell Science (Shanghai Institute of Biochemistry and Cell Biology) of the Chinese Academy of Sciences, in collaboration with Prof. LI Wenfeng from Wenzhou Medical University and Prof. LI Guohui from Liaoning Normal University, uncovered a novel EGFR mutant (EGFR R252C), revealing its function in promoting tumor progression through direct phosphorylation and activation of ERK1/2, and confirmed the clinical therapeutic potential of afatinib against tumors harboring this mutation.
The starting point of this study was a patient simultaneously diagnosed with lung cancer and brain glioma. Through genetic sequencing, the research team identified a rare EGFR mutation in the patient's tumor samples: the substitution of arginine (R) at position 252 in the extracellular region with cysteine (C), i.e., EGFR R252C. Notably, although this mutation has been recorded in public cancer genome databases, its specific biological function and mechanism in tumors remained unclear. Thus, investigating whether and how EGFR R252C drives tumor growth constituted the core scientific question of this study.
In the traditional understanding, after binding with its ligand EGF, EGFR can dimerize and undergo autophosphorylation, thereby initiating downstream signaling pathways. This study found that, in the absence of ligand binding, the R252C mutation acts like a "molecular lock," directly tethering two EGFR molecules together via a newly formed disulfide bond (C252-C252) to form a stable dimer. This abnormal dimerization induces conformational changes in the EGFR receptor. Consequently, the mutated EGFR itself exhibits minimal autophosphorylation, yet it can bypass the classical steps, directly bind to the key downstream signaling molecules ERK1/2, phosphorylate and activate ERK1/2, thereby promoting tumor cell proliferation and tumor growth in vivo.
Through further drug screening and analysis, they discovered that the second-generation EGFR tyrosine kinase inhibitor Afatinib can effectively inhibit ERK1/2 activation and tumor growth driven by the EGFR R252C mutation. In the case study of this patient, the use of Afatinib successfully controlled the progression of the multifocal lung cancer and glioma, extending the progression-free survival period.
This research not only explains the oncogenicity of this rare EGFR mutation at the mechanistic level but also provides a directly actionable treatment option for patients carrying this mutation, holding promise for rapid clinical translation and patient benefit.
Reference: https://www.nature.com/articles/s41467-026-68699-4
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