Comprehensive Stability Analysis of EGFR Related to Non-Small Cell Lung Cancer

Abstract

Lung cancer is the predominant cause of cancer deaths on a worldwide scale. A specific change in a protein called epidermal growth factor receptor (EGFR) can cause a point mutation or complex mutation (deletion and insertion), which is the root cause of non-small cell lung cancer (NSCLC). The survival rate of the non-small cell lung cancer (NSCLC) positive patients is increasing with the improvements in the field of computational and clinical biology. Many NSCLC cases arise from the L858R mutation, where leucine (L) is replaced by arginine (R) at the 858th position in the EGFR, and that is also recognized as an exon 21 substitution. Moreover, 60% of the EGFR-mutated lung cancer patients develop acquired resistance to the first-generation EGFR tyrosine kinase inhibitors (TKIs) due to another mutation T790M. This thesis analyzes the stability variation of diverse stages of EGFR mutations found in NSCLC using different computational methods. This thesis (a) investigates the changes in hydrogen bonds of the EGFR-ErbB3 heterodimer related to non-small cell lung cancer and drug resistance, (b) explores the stability variations at critical positions of EGFR related to NSCLC, (c) comprehensively analyzes the stability for different non-small cell lung cancer-causing EGFR homodimer and heterodimers, (d) investigates a potential FDA-approved drug as a suitable inhibitor for SARS-CoV-2. In these studies, modeling techniques are employed to generate structures of EGFR with several mutations, and molecular dynamics (MD) simulations are used to reveal the dynamic states of the molecules. These data, for each EGFR mutational complex, are the foundation of our research analysis, from which various characteristics of molecules were uncovered through a series of modeling and learning techniques.

Indicatively, we performed molecular dynamic (MD) simulations of the EGFR-ErbB3 dimer for its wild type, L858R, and L858R_T790M mutational structures and analyzed the changes in their hydrogen bonds which makes a significant contribution to protein's overall stability. We researched the potential reason behind the L858R and L858R_T790M mutation to occur precisely at the 858th and 790th position of the EGFR, respectively. Based on the results of MD simulation, we also established how FDA-approved drug Ivermectin could bind in a better way than other renowned drugs, with coronavirus causing protease. We did structural displacement analysis to find the least flexible and more stable structure of the protease. We considered two heterodimers (EGFR-CMET and EGFR-ErbB2) and one homodimer (EGFR-EGFR) and formed the hydrogen-bond network matrices. Then we used those networks to track their behavioral changes for their wild type, L858R, L858R_T790M mutational structures individually. Further, we studied how eigenvalues and eigenvectors are changing in the network to prove the stability changes for different structures. Overall, these studies will lead to a better understanding of the dynamic features of EGFR mutations and provide new insights to study and predict drug resistance/sensitivity in the treatment of NSCLC. The analytical results regarding the stability issues convey much valuable information that will be beneficial to the design of future targeted therapies and innovative drug discovery and by other researchers to study NSCLC further and by medical doctors as a reference for NSCLC treatment. Finally, we researched the potentiality of Ivermectin to fight against coronavirus, which could help to bring the global pandemic under control.

Date of Award	25 Aug 2020
Original language	English
Awarding Institution	City University of Hong Kong
Supervisor	Hong YAN (Supervisor)