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- Title
Structural signature of the G719S-T790M double mutation in the EGFR kinase domain and its response to inhibitors.
- Authors
Doss, C. George Priya; Rajith, B.; Chakraborty, Chiranjib; NagaSundaram, N.; Ali, Shabana Kouser; Hailong Zhu
- Abstract
Some individuals with non-small-cell lung cancer (NSCLC) benefit from therapies targeting epidermal growth factor receptor (EGFR), and the characterization of a new mechanism of resistance to the EGFR-specific antibody gefitinib will provide valuable insight into how therapeutic strategies might be designed to overcome this particular resistance mechanism. The G719S and T790M mutations and their combination were involved in causing different conformational redistribution of EGFR. In the present computational study, we analyzed the impact and structural influence of G719S/T790M double mutation (DM) in EGFR with ligand (gefitinib) through molecular dynamic simulation (50 ns) and docking analysis. We observed the escalation in distance between the functional loop and activation loop with respect to T790M mutation compared to the G719S mutation. Furthermore, we confirmed that the G719S mutation causes the ligand to move closer to the hinge region, whereas T790M makes the ligand escape from the binding pocket. Obtained results provide with an explanation for the resistance induced by T790M and a vital clue for the design of drugs to combat gefitinib resistance.
- Subjects
CANCER treatment; SMALL cell lung cancer; EPIDERMAL growth factor receptors regulation; EPIDERMAL growth factor receptor genetics; KINASE inhibitors; GENE therapy; THERAPEUTICS
- Publication
Scientific Reports, 2014, p1
- ISSN
2045-2322
- Publication type
Article
- DOI
10.1038/srep05868