Structure and Dynamics of the EGF Receptor as Revealed by Experiments and Simulations and Its Relevance to Non-Small Cell Lung Cancer

Abstract

The epidermal growth factor receptor (EGFR) is historically the prototypical receptor tyrosine kinase, being the first cloned and the first where the importance of ligand-induced dimer activation was ascertained. However, many years of structure determination has shown that EGFR is not completely understood. One challenge is that the many structure fragments stored at the PDB only provide a partial view because full-length proteins are flexible entities and dynamics play a key role in their functionality. Another challenge is the shortage of high-resolution data on functionally important higher-order complexes. Still, the interest in the structure/function relationships of EGFR remains unabated because of the crucial role played by oncogenic EGFR mutants in driving non-small cell lung cancer (NSCLC). Despite targeted therapies against EGFR setting a milestone in the treatment of this disease, ubiquitous drug resistance inevitably emerges after one year or so of treatment. The magnitude of the challenge has inspired novel strategies. Among these, the combination of multi-disciplinary experiments and molecular dynamic (MD) simulations have been pivotal in revealing the basic nature of EGFR monomers, dimers and multimers, and the structure-function relationships that underpin the mechanisms by which EGFR dysregulation contributes to the onset of NSCLC and resistance to treatment.

JMJD8 Promotes Malignant Progression of Lung Cancer by Maintaining EGFR Stability and EGFR/PI3K/AKT Pathway Activation

“…EGFR can regulate the cycle of lung cancer cells through signal transduction pathways, promote tumor cell proliferation, induce angiogenesis, and promote tumor spread and metastasis. Accordingly, EGFR can reduce the killing effect of cytotoxic drugs on tumor cells 6 , 7 . The EGFR protein is divided into three domains: the extracellular ligand-binding domain, the transmembrane domain, and the intracellular kinase domain.…”

Epiregulin promotes hair growth via EGFR‐medicated epidermal and ErbB4‐mediated dermal stimulation

“…It has been reported that EREG had a binding affinity for both EGFR and ErbB4 10,13 . The ErbB family comprises four homologous RTKs.…”

De Novo T790M Mutation in an L858R Epidermal Growth Factor Receptor Mutant-Associated Lung Adenocarcinoma

“…However, a recent study showed that the T790M mutation causes drug resistance by enhancing the ATP affinity of the oncogenic L858R mutant [ 24 ]. Mutation-related changes in the stability of ligand-independent dimerization of the EGFR receptor may also play role in drug resistance [ 25 ]. Overall, this study showed that mice carrying inducible lung-specific L858R-hEGFR or [L858R+T790M]-hEGFR transgene containing the full-length of genomic EGFR developed lung adenocarcinomas and that L858R-hEGFR-associated lung adenocarcinomas acquired de novo T790 mutation without previous TKI therapy.…”