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The Epidermal Growth Factor Receptor (EGFR) is a driver gene that is amplified in more than half of all glioblastomas. After the initial high copy-number amplification, secondary missense mutations in the extracellular, ligand binding domain of EGFR can evolve. We here performed analysis on these mutations to better understand their function. METHODS Activation of EGFR-mutation constructs was measured by western blot and high-throughput quantitative image analysis using EGFR and phospho-EGFR specific antibodies. RESULTS Amphiregulin (AREG) is a low affinity EGFR ligand and was able to only marginally activate EGFRwt at high concentrations. In contrast however, AREG strongly activated all extracellular domain (ECD) mutation constructs (R108K, A289V and G598V). As expected, EGF-stimulation resulted in a strong activation in both EGFRwt and ECD mutation constructs. Further dose response analysis showed that in EGFRwt, all high affinity EGFR ligands (EGF, TGFa, HB-EGF and BTC) resulted in a strong activation and all low affinity ligands AREG, EREG and EPGN resulted in a markedly weaker activation. All ECD mutations however, showed strong activation towards all EGFR ligands, including the low affinity ligands (40%-80% of EGF stimulation). The constitutively active, ligand independent EGFRvIII mutation did not respond to any of the ligands and was mainly found to have an intracellular localization. Interestingly, the presence of ECD mutations and EGFRvIII are inversely correlated: in three large datasets (TCGA, Belob and Intellance 2), the majority of samples expressing EGFRvIII do not express additional ECD mutations and vice versa. ECD mutations likely affect stability of the tethered, inactive conformation thereby increasing exposure of the dimerization domain (II), resulting in increased ligand-sensitivity. CONCLUSION These experiments show that EGFR containing extracellular missense mutations render the receptor more sensitive to stimulation by low affinity ligands. Glioblastomas evolve to either become independent of ligand (EGFRvIII) or become ligand-hypersensitive (ECD mutations).

CSIG-08. EXTRACELLULAR DOMAIN MUTATIONS IN EGFR RESULT IN A HYPERSENSITIVE RECEPTOR