Stability Investigation Using Hydrogen Bonds for Different Mutations and Drug Resistance in Non-Small Cell Lung Cancer Patients

Abstract

Lung cancer is the predominant reason for cancer deaths. Deletion mutation (del_E746-A750) in the Epidermal growth factor receptor (EGFR) is liable for 40% of Non-small cell lung cancer (NSCLC). However, 70% of the NSCLC active patients acquire T790M drug resistance mutation after progressing with the first-line EGFR Tyrosine kinase inhibitor (TKI). There are many third-generation EGFR-TKIs which are EGFR mutant selective and produced to heal the patients with T790M resistance mutation. Osimertinib is one of the third-generation EGFR TKIs which irreversibly inhibits the EGFR activity after the T790M mutation. Unfortunately, despite having an impressive initial response, 6 out of 15 patients who were diagnosed with third-generation EGFR-TKI would develop a new resistance and the most frequent being C797S mutation at exon 20. Numerous treatment techniques were implemented for patients who have progressed with C797S second resistance mutation, but there is no official fourth-generation EGFR TKI has invented. In our research work, we analyzed the stability changes for each structure in terms of reduction and hydrogen bonds. Our findings provide insight into the diversity of mechanisms through hydrogen bond analysis in different EGFR structures in terms of stability check and highlight the need for therapeutics and fourth-generation TKI to overcome resistance arbitrated by EGFR C797S.