Glioblastoma mutations alter EGFR dimer structure to prevent ligand bias

Chun Hu, Carlos A. Leche, Anatoly Kiyatkin, Zhaolong Yu, Steven E. Stayrook, Kathryn M. Ferguson and Mark A. Lemmon ()
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Chun Hu: Yale University School of Medicine
Carlos A. Leche: Yale University School of Medicine
Anatoly Kiyatkin: Yale University School of Medicine
Zhaolong Yu: Yale University
Steven E. Stayrook: Yale University School of Medicine
Kathryn M. Ferguson: Yale University School of Medicine
Mark A. Lemmon: Yale University School of Medicine

Nature, 2022, vol. 602, issue 7897, 518-522

Abstract: Abstract The epidermal growth factor receptor (EGFR) is frequently mutated in human cancer1,2, and is an important therapeutic target. EGFR inhibitors have been successful in lung cancer, where mutations in the intracellular tyrosine kinase domain activate the receptor1, but not in glioblastoma multiforme (GBM)3, where mutations occur exclusively in the extracellular region. Here we show that common extracellular GBM mutations prevent EGFR from discriminating between its activating ligands4. Different growth factor ligands stabilize distinct EGFR dimer structures5 that signal with different kinetics to specify or bias outcome5,6. EGF itself induces strong symmetric dimers that signal transiently to promote proliferation. Epiregulin (EREG) induces much weaker asymmetric dimers that drive sustained signalling and differentiation5. GBM mutations reduce the ability of EGFR to distinguish EREG from EGF in cellular assays, and allow EGFR to form strong (EGF-like) dimers in response to EREG and other low-affinity ligands. Using X-ray crystallography, we further show that the R84K GBM mutation symmetrizes EREG-driven extracellular dimers so that they resemble dimers normally seen with EGF. By contrast, a second GBM mutation, A265V, remodels key dimerization contacts to strengthen asymmetric EREG-driven dimers. Our results argue for an important role of altered ligand discrimination by EGFR in GBM, with potential implications for therapeutic targeting.

Date: 2022
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DOI: 10.1038/s41586-021-04393-3

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