Abstract
The EGFR gene is one of the most frequently mutated and/or amplified gene both in lung adenocarcinomas (LUAD) and in glioblastomas (GBMs). Although both tumor types depend on the mutation for growth, clinical benefit of EGFR tyrosine kinase inhibitors (TKIs) has only been observed in LUAD patients and, thus-far, not in GBM patients. Also in LUAD patients however, responses are restricted to specific EGFR mutations only and these ‘TKI-sensitive’ mutations hardly occur in GBMs. This argues for mutation-specific (as opposed to tumor-type specific) responses to EGFR-TKIs. We here discuss potential reasons for the differences in mutation spectrum and highlight recent evidence for specific functions of different EGFR mutations. These mutation-specific effects likely underlie the differential treatment response between LUAD and GBMs and provide new insights into how to target EGFR in GBM patients.
Highlights
More than fifty years ago, Stanley Cohen reported on the isolation of a heat-stable protein from mouse salivary glands that was able to induce the eruption of incisors and separation of the eyelids [1].Later studies showed that the eyelid separation was a consequence of enhanced keratinization and growth of the epidermis and, based on this function, the protein was coined epidermal growth factor (EGF) [2,3]
Because of the clinical responses observed in EGF receptor (EGFR)-mutated lung adenocarcinomas (LUAD) patients, and because of the high frequency of EGFR mutations in GBMs, it was logical to test the clinical efficacy of EGFR-tyrosine kinase inhibitors (TKIs) in GBM patients
We have demonstrated that EGFRwt, EGFRL858R and EGFRvIII each bind to a unique set of proteins and activate different molecular pathways [63]
Summary
More than fifty years ago, Stanley Cohen reported on the isolation of a heat-stable protein from mouse salivary glands that was able to induce the eruption of incisors and separation of the eyelids [1]. They bind to the extracellular leucine rich domains I and III, and this association results in the exposure of the cysteine rich domain II, which allows for receptor dimerization. Phosphorylation occurs on multiple sites: the intracellular domain contains twenty tyrosine residues, twelve of which can be phosphorylated following ligand binding [7]. This phosphorylation results in the recruitment of Cancers 2018, 10, 489; doi:10.3390/cancers10120489 www.mdpi.com/journal/cancers. The EGF receptor (EGFR) was identified based on its affinity for EGF, later studies showed it can be activated by six other, related- ligands: heparin-binding EGF-like growth factor (HB-EGF), amphiregulin, epiregulin, epigen, betacellulin and transforming growth factor-alpha (TGF-α) [10]. Each ligand can induce quantitative differences in responses, but can elicit ligand-specific responses [10,11]
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