Mutational analysis of epidermal growth factor receptor tyrosine kinase and the structural basis of its inhibition in prevention of non-small cell lung cancer
Ssuuna, Kenneth Mark
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Background: Lung cancer is among the commonest cancers with the highest mortality in the world and the mostly diagnosed cancer in developing countries. Non-Small Cell Lung Cancer is the type that accounts for most of the lung cancer cases. It is believed that mutational activation of the Epidermal Growth Factor Receptor-Tyrosine Kinase (EGFR-TK), a transmembrane glycoprotein responsible for regulating signalling pathways controlling cellular proliferation, is a key reason for lung cancer progression. These clinically significant mutations commonly occur in exon 19 and exon 21 of the EGFR-TK gene. However, studies have shown lung cancer cases with these mutations are responsive to EGFR-TK Inhibitor (EGFR-TKI) drugs. The most common and essential EGFR-TKIs used in lung cancer treatment are Erlotinib and Gefitinib. Objective: To identify clinically significant mutations and potential ligand binding sites in the EGFR-TK domain essential in the development of inhibitors as therapeutics to NSCLC. Methodology: Using the Genome Data Viewer, a genome browser by the National Centre for Biotechnology Information (NCBI), the EGFR gene was browsed from the human genome. Protein structures bound to common inhibitor drugs were downloaded from the Protein Data Bank. File 1M17 had EGFR bound to Erlotinib while file 3UG2 had EGFR bound to Gefitinib. Using Jmol molecular viewer, the structures were analyzed. Results: Significant mutations obtained were five over-lapping short in-frame deletions in exon 19 and two substitution mutations leading to Leucine to Arginine amino acid change in exon 21. Results from structural analysis indicated that Erlotinib and Gefitinib interacted more with Leucine amino acid than any other amino acid in their respective inhibition sites. Erlotinib interacted with Leucine amino acids at codons 694, 764 and 820 whereas Gefitinib interacted with Leucine amino acids at codons 718, 788 and 844. This identified Leucine as a significant amino acid during the drug interactions compared to other amino acids thus crucial in drug development. Conclusion: The mutation study provided information about the significant mutations that occur in EGFR gene that is essential in determination of secondary mutations that would cause resistance to the existing drugs whereas the structural analysis provided information regarding the significant amino acids in EGFR that are essential in development of new therapeutic drugs for use in prevention of lung cancer particularly Non-Small Cell Lung Cancer.