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

TL;DR

A new EGFR mutation in the extracellular domain promotes cancer growth by activating ERK and can be treated with afatinib.

Contribution

The study reveals a novel mechanism of EGFR activation via the R252C mutation in the extracellular domain.

Findings

The R252C mutation causes disulfide-mediated EGFR dimerization and conformational change.

EGFR R252C activates ERK1/2 directly, promoting tumor cell proliferation and growth.

Afatinib effectively suppresses tumor growth in patients with this mutation.

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.

While EGFR mutations are drivers of cancer, the function of extracellular domain mutations remains poorly defined. Here, the authors show that the R252C extracellular mutation induces conformational change of EGFR to directly activate ERK and promote cancer growth, which can be targeted by afatinib.

Figures