Identification of High-Risk Single Nucleotide Polymorphisms (SNPs) of Epidermal Growth Factor Receptor (EGFR) and Their Interaction with Various TKI Drugs

Objectives: Epidermal growth factor receptor (EGFR) is the membrane receptor of tyrosine kinase family that plays crucial role in cell growth, cell division and cell survival. Upregulation of EGFR gene has been seen in various cancer types due to mutations. As non-synonymous single nucleotide polymorphisms (nsSNPs) are responsible for half of the genetic variations that are responsible of human diseases, it is crucial to analyze putative functional nsSNPs. Therefore, we aimed to identify nsSNPs of EGFR gene and evaluate their effect on its protein receptor. We also docked the mutant type protein structures with common tyrosine kinase inhibitor (TKIs) to showcase their stability with one another. Methods: We observed five novel nsSNPs (E330K, K745R, R962H, R675Q and S752Y) that are present in different domains of EGFR using various bioinformatics tools and simultaneously predicted their deleterious effects on EGFR. Furthermore, docking studies were carried out with three of the common TKIs (erlotinib, gefitinib, canertinib). Results: Mutant type K745R was predicted to be potentially more damaging than other mutants due to its presence in highly conserved region of EGFR protein receptor and its ability to affect protein stability. Conclusion: As this study is the first comprehensive study of these novel nsSNPs of EGFR, the results of this study would be crucial for future studies, drug discovery and development of personalized medicine. Although along with in-silico characterisation of nsSNPs clinical population-based studies are essential.