EGFR Mutations in GBM Alter Ligand Binding and Subsequent Dimerization

In glioblastoma (GBM), mutations in EGFR occur in approximately 24% of cases, yet EGFR inhibitors have poor efficacy in this disease. EGFR mutations are exclusively extracellular in GBM, and Hu and colleagues investigated if they exert their effects by altering EGFR's ability to distinguish between its activating ligands. Using small-angle X-ray scattering (SAXS), wild-type EGFR was found to dimerize strongly with EGF but not with epiregulin (EREG), a low-affinity EGFR ligand. In contrast, L38R, R84K, A265V, or A265T mutations displayed full dimerization with either EGF or EREG, which was also confirmed in cross-linking experiments. Further cross-linking studies showed that amphiregulin-dependent EGFR dimerization was also increased by R84K or A265V mutations, as was epigen-induced dimerization. However, these effects were not observed with the high-affinity ligand transforming growth factor-α (TGFα). By determining a 2.9 Å resolution crystal structure, it was shown that the R84K mutation leads to a symmetric dimer of EGFR after EREG binding, resembling those induced by the high-affinity ligands EGF and TGFα. Specifically, this occurs as the R84K mutation supports breakage of “autoinhibitory” R84-A265 and L38-F263 contacts upon EREG ligand binding, leading to symmetry and strengthening of the dimer. Moreover, mutations at R84 lead to equalizing of the EREG-binding sites, which also increases the EREG-binding affinity by nearly tenfold. Similar effects are suggested for other EGFR mutations common to GBM such as L38R. Additionally, structural investigation into the mechanisms by which A265V strengthens EREG-induced dimers indicated that this mutation modifies the pocket for Y251 of the opposing dimer, ultimately allowing it to dock more effectively even in an asymmetric dimer. Overall, this study provides a structural model that reveals how EGFR mutations in GBM alter ligand discrimination by the receptor and provides guidance on ways of devising new therapeutic approaches to target these mutations in this disease.

Hu C, Leche CA 2nd, Kiyatkin A, Yu Z, Stayrook SE, Ferguson KM, et al. Glioblastoma mutations alter EGFR dimer structure to prevent ligand bias. Nature 2022;602:518–22.

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