The coevolutionary landscape of drug resistance in epidermal growth factor receptor: A cancer perspective

Epidermal growth factor receptor (EGFR), the first receptor tyrosine kinase, plays a critical role in neoplastic metastasis, angiogenesis, tumor invasion, and apoptosis, making it a prime target for treating non-small cell lung cancer (NSCLC). Although tyrosine kinase inhibitors (TKIs) have shown high efficacy and promise for cancer patients, resistance to these drugs often develops within a year due to alterations. The present study investigates the compensatory alterations in EGFR to understand the evolutionary process behind drug resistance. Our findings reveal that coevolutionary alterations expand the drug-binding pocket; leading to reduced drug efficacy and suggested that such changes significantly influence the structural adaptation of the EGFR against these drugs. Analysis such as root mean square deviation (RMSD), root mean square fluctuation (RMSF), solvent accessible surface area (SASA), principal component analysis (PCA), and free energy landscape (FEL) demonstrated that structures of wild EGFR docked with gefitinib are more stable which suggests its susceptibility towards drug than coevolution dependent double mutant. The findings were supported by MM-GBSA binding affinity analysis. The insights from this study highlighted the evolution-induced structural changes which contributes to drug resistance in EGFR and may certainly aid in designing more effective drugs.