Glioblastoma mutations alter EGFR dimer structure to prevent ligand bias

The epidermal growth factor receptor (EGFR) is frequently mutated in human cancer^1,2, 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 outcome^5,6. 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.