Coevolution-based computational approach to detect resistance mechanism of epidermal growth factor receptor

Abstract

Tyrosine kinase epidermal growth factor receptor (EGFR) correlates the neoplastic cell metastasis, angiogenesis, neoplastic incursion, and apoptosis. Due to the involvement of EGFR in these biological processes, it becomes a most potent target for treating non-small cell lung cancer (NSCLC). The tyrosine kinase inhibitors (TKI) have endorsed high efficacy and anticipation to patients but unfortunately, within a year of treatment, drug targets develop resistance due to mutations. The present study detected the compensatory mutations in EGFR to know the evolutionary mechanism of drug resistance. The results of this study demonstrate that compensatory mutations enlarge the drug-binding pocket which may lead to the altered orientation of the ligand (gefitinib and erlotinib) causing drug resistance. This indicates that coevolutionary forces play a significant role in fine-tuning the structure of EGFR protein against the drugs. The analysis provides insight into the evolution-induced structural aspects of drug resistance changes in EGFR which in turn be useful in designing drugs with better efficacy.