Structural basis of the effect of activating mutations on the EGF receptor.

Ioannis Galdadas,Luca Carlino,Richard A Ward,Samantha J Hughes,Francesco Luigi Gervasio,Shozeb Haider

doi:10.7554/elife.65824

Abstract

Mutations within the kinase domain of the epidermal growth factor receptor (EGFR) are common oncogenic driver events in non-small cell lung cancer. Although the activation of EGFR in normal cells is primarily driven by growth-factor-binding-induced dimerization, mutations on different exons of the kinase domain of the receptor have been found to affect the equilibrium between its active and inactive conformations giving rise to growth-factor-independent kinase activation. Using molecular dynamics simulations combined with enhanced sampling techniques, we compare here the conformational landscape of the monomers and homodimers of the wild-type and mutated forms of EGFR ΔELREA and L858R, as well as of two exon 20 insertions, D770-N771insNPG, and A763-Y764insFQEA. The differences in the conformational energy landscapes are consistent with multiple mechanisms of action including the regulation of the hinge motion, the stabilization of the dimeric interface, and local unfolding transitions. Overall, a combination of different effects is caused by the mutations and leads to the observed aberrant signaling.

Highlights

The epidermal growth factor receptor (EGFR) is a cell surface receptor, which regulates cell proliferation and differentiation by phosphorylating downstream signaling proteins (Sigismund et al, 2018; Wee and Wang, 2017)
EGFR in-frame deletions in exon 19 are the most prevalent of EGFR kinase domain mutations accounting for 45% of EGFR mutations in non-small cell lung cancer (NSCLC), followed by the L858R missense mutation in exon 21, which accounts for approximately 40–45% of EGFR kinase domain mutations (Sharma et al, 2007)
Consistent with their purported role in the etiology of NSCLC, recent studies have shown that b3aC DELREA, L858R, A763-Y764insFQEA, and D770-N771insNPG mutated EGFR proteins are oncogenic in both cell cultures and transgenic mouse models (Ji et al, 2006; Politi et al, 2006; Sordella et al, 2004; Xu et al, 2007; Yasuda et al, 2013)

Summary

Introduction

The epidermal growth factor receptor (EGFR) is a cell surface receptor, which regulates cell proliferation and differentiation by phosphorylating downstream signaling proteins (Sigismund et al, 2018; Wee and Wang, 2017). Exon 20 insertions (Ex20Ins) collectively account for the third most common category of EGFR mutations found in NSCLC and are detected in 4–10% of the cases (Arcila et al, 2013; Yasuda et al, 2012) Consistent with their purported role in the etiology of NSCLC, recent studies have shown that b3aC DELREA, L858R, A763-Y764insFQEA, and D770-N771insNPG mutated EGFR proteins are oncogenic in both cell cultures and transgenic mouse models (Ji et al, 2006; Politi et al, 2006; Sordella et al, 2004; Xu et al, 2007; Yasuda et al, 2013).

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