Stability Analysis at Key Positions of EGFR Related to Non-small Cell Lung Cancer

Author(s): Avirup Ghosh*, Hong Yan

Journal Name: Current Bioinformatics

Volume 15 , Issue 3 , 2020

Become EABM
Become Reviewer

Graphical Abstract:


Background: Mutations in a protein called the Epidermal Growth Factor Receptor (EGFR) can cause Non-Small Cell Lung Cancer (NSCLC), which is the most common form of lung cancer. 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, half of the EKFR-mutated lung cancer patients develop acquired resistance to the first-generation EGFR-TKIs due to another mutation T790M.

Objective: In this research work, a novel method is used to investigate the possible reason for the EGFR mutation to takes place in the specific 858th and 790th position, and also, we evaluated the hydrogen bonds to measure the overall stability of different structures.

Methods: We performed the molecular dynamics simulation and used Amber tool to achieve our primary objectives and later we use CPPTRAJ to analyze other changes in the hydrogen bonds for different mutational structures of EGFR.

Results: First, we investigated the hydrogen bonds in different positions in the EGFR kinase domain and estimated why the first stage mutation (L858R) and resistance mutation (L858R/T790M) take place in the 858th and 790th position respectively. We found the hydrogen bond counts in the 858th and 790th position is lesser than the neighborhood positions and that yields to achieve a least stability in that position.

Conclusion: Our method represents an important contribution to molecular dynamics analysis for NSCLC studies. The results obtained from this study provide a useful insight into the NSCLC drug resistance.

Keywords: EGFR, Non-Small Cell Lung Cancer (NSCLC), gene mutation, stability analysis, molecular dynamics analysis, kinase.

Zou B, Wang DD, Ma L, Chen L, Yan H. Analysis of the relationship between lung cancer drug response level and atom connectivity dynamics based on trimmed Delaunay triangulation. Chem Phys Lett 2016; 652: 117-22.
Chanvorachote P, Chunhacha P. Lung cancer metastasis. In: Introduction to Cancer Metastasis. 2016; p. 61.
Freedman ND, Leitzmann MF, Hollenbeck AR, Schatzkin A, Abnet CC. Cigarette smoking and subsequent risk of lung cancer in men and women: analysis of a prospective cohort study. Lancet Oncol 2008; 9(7): 649-56.
[] [PMID: 18556244]
Sasco AJ, Secretan MB, Straif K. Tobacco smoking and cancer: a brief review of recent epidemiological evidence. Lung Cancer 2004; 45(Suppl. 2): S3-9.
[] [PMID: 15552776]
Greulich H, Chen TH, Feng W, et al. Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants. PLoS Med 2005; 2(11) e313
[] [PMID: 16187797]
Bar J, Onn A. Overcoming molecular mechanisms of resistance to first-generation epidermal growth factor receptor tyrosine kinase inhibitors. Clin Lung Cancer 2012; 13(4): 267-79.
[] [PMID: 22154113]
Available from. Accessed on 21 November 2019.
Mitsudomi T, Yatabe Y. Epidermal growth factor receptor in relation to tumor development: EGFR gene and cancer. FEBS J 2010; 277(2): 301-8.
[] [PMID: 19922469]
Ladanyi M, Pao W. Lung adenocarcinoma: guiding EGFR-targeted therapy and beyond. Mod Pathol 2008; 21(Suppl. 2): S16-22.
[] [PMID: 18437168]
Crinò L, Weder W, van Meerbeeck J, Felip E, Group EGW. ESMO Guidelines Working Group. Early stage and locally advanced (non-metastatic) non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010; 21(Suppl. 5): v103-15.
[] [PMID: 20555058]
Masters GA, Temin S, Azzoli CG, et al. American society of clinical oncology clinical practice. American society of clinical oncology clinical practice. Systemic therapy for stage IV non–small-cell lung cancer: American society of clinical oncology clinical practice guideline update. J Clin Oncol 2015; 33(30): 3488-515.
[] [PMID: 26324367]
Ghosh A, Yan H. Hydrogen bond analysis of the EGFR-ErbB3 heterodimer related to non-small cell lung cancer and drug resistance. J Theor Biol 2019; 464: 63-71.
[] [PMID: 30593826]
Sequist LV, Yang JCH, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013; 31(27): 3327-34.
[] [PMID: 23816960]
Cross DA, Ashton SE, Ghiorghiu S, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov 2014; 4(9): 1046-61.
[] [PMID: 24893891]
Jänne PA, Yang JCH, Kim DW, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med 2015; 372(18): 1689-99.
[] [PMID: 25923549]
Piotrowska Z, Sequist LV. Epidermal growth factor receptor–mutant lung cancer: new drugs, new resistance mechanisms, and future treatment options. Cancer J 2015; 21(5): 371-7.
[] [PMID: 26389761]
Grabe T, Lategahn J, Rauh D. C797S Resistance: The undruggable egfr mutation in non-small cell lung cancer? ACS Med Chem Lett 2018; 9(8): 779-82.
[] [PMID: 30128066]
Ma L, Wang DD, Huang Y, Yan H, Wong MP, Lee VHF. EGFR mutant structural database: computationally predicted 3D structures and the corresponding binding free energies with gefitinib and erlotinib. BMC Bio inform 2015; 16-85.
Scott WJ, Howington J, Feigenberg S, Movsas B, Pisters K. American college of chest physicians. Treatment of non-small cell lung cancer stage I and stage II:. ACCP evidence-based clinical practice guidelines 2nd edition. Chest 2007; 132(Suppl 3): 234S-42S.
Ghosh A, Yan H. Hydrogen bond analysis of the EGFR-ErbB3 heterodimer related to non-small cell lung cancer and drug resistance J Theor Biol 464: 63-71. 201
The PyMOL Molecular Graphics System Version 20 Schrödinger, LLC.
Case DA, Ben-Shalom IY, Brozell SR, et al. AMBER. University of California, San Francisco 2018.
Chen NY. The biological functions of low-frequency phonons. Sci Sin 1977. 20447457
Zhou GP. Biological functions of soliton and extra electron motion in DNA structure. Phys Scr 1989; 40: 698-701.
Chou KC, Mao B. Collective motion in DNA and its role in drug intercalation. Biopolymers 1988; 27(11): 1795-815.
[] [PMID: 3233332]
Chou KC, Maggiora GM, Mao B. Quasi-continuum models of twist-like and accordion-like low-frequency motions in DNA. Biophys J 1989; 56(2): 295-305.
[] [PMID: 2775828]
Martel P. Biophysical aspects of neutron scattering from vibrational modes of proteins. Prog Biophys Mol Biol 1992; 57(3): 129-79.
[] [PMID: 1603938]
Chou KC. Low-frequency collective motion in biomacromolecules and its biological functions. Biophys Chem 1988; 30(1): 3-48.
[] [PMID: 3046672]
Chen NY, Forsen S. The biological functions of low-frequency phonons: 2. Cooperative effects. Chem Scr 1981; 18: 126-32.
Wang JF, Chou KC. Insight into the molecular switch mechanism of human Rab5a from molecular dynamics simulations. Biochem Biophys Res Commun 2009; 390(3): 608-12.
[] [PMID: 19819222]
Chou KC, Zhang CT, Maggiora GM. Solitary wave dynamics as a mechanism for explaining the internal motion during microtubule growth. Biopolymers 1994; 34(1): 143-53.
[] [PMID: 8110966]
Gordon G. Extrinsic electromagnetic fields, low frequency (phonon) vibrations, and control of cell function: a non-linear resonance system. J Biomed Sci Eng 2008; 1: 152-6.
Madkan A, Blank M, Elson E, Geddis MS, Goodman R. Steps to the clinic with ELF EMF. Nat Sci 2009; 1: 157-65.
Available from. Accessed on 21, November 2019.
Wang DD, Zhou W, Yan H, Wong M, Lee V. Personalized prediction of EGFR mutation-induced drug resistance in lung cancer. Sci Rep 2013; 3(2855): 2855.
[] [PMID: 24092472]
Mitchell JBO, Price SL. On the relative strengths of amide.amide and amide.water hydrogen bonds. Chem Phys Lett 1991; 180: 517-23.
Pace CN, Fu H, Fryar KL, et al. Contribution of hydrogen bonds to protein stability. Protein Sci 2014; 23(5): 652-61.
Baker EN, Hubbard RE. Hydrogen bonding in globular proteins. Prog Biophys Mol Biol 1984; 44(2): 97-179.
[] [PMID: 6385134]
McDonald IK, Thornton JM. Satisfying hydrogen bonding potential in proteins. J Mol Biol 1994; 238(5): 777-93.
[] [PMID: 8182748]
Roe DR, Cheatham TE III. PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data. J Chem Theory Comput 2013; 9(7): 3084-95.
[] [PMID: 26583988]
Xu X, Wang X, Xiao Z, Li Y, Wang Y. Probing the structural and functional link between mutation- and pH-dependent hydration dynamics and amyloidosis of transthyretin. Soft Matter 2012; 8: 324-36.
Xu X, Ma Z, Wang X, et al. Water’s potential role: Insights from studies of the p53 core domain. J Struct Biol 2012; 177(2): 358-66.
[] [PMID: 22197648]
Chou KC. Structural bioinformatics and its impact to biomedical science. Curr Med Chem 2004; 11(16): 2105-34.
[] [PMID: 15279552]
Chou KC, Jones D, Heinrikson RL. Prediction of the tertiary structure and substrate binding site of caspase-8. FEBS Lett 1997; 419(1): 49-54.
[] [PMID: 9426218]
Chou KC, Tomasselli AG, Heinrikson RL. Prediction of the tertiary structure of a caspase-9/inhibitor complex. FEBS Lett 2000; 470(3): 249-56.
[] [PMID: 10745077]
Chou KC. Insights from modelling the 3D structure of the extracellular domain of alpha7 nicotinic acetylcholine receptor. Biochem Biophys Res Commun 2004; 319(2): 433-8.
[] [PMID: 15178425]
Chou KC, Wei DQ, Zhong WZ. Binding mechanism of coronavirus main proteinase with ligands and its implication to drug design against SARS. Biochem Biophys Res Commun 2003; 308(1): 148-51.
[] [PMID: 12890493]
Huang RB, Du QS, Wang CH, Chou KC. An in-depth analysis of the biological functional studies based on the NMR M2 channel structure of influenza A virus. Biochem Biophys Res Commun 2008; 377(4): 1243-7.
[] [PMID: 18996090]
Li XB, Wang SQ, Xu WR, Wang RL, Chou KC. Novel inhibitor design for hemagglutinin against H1N1 influenza virus by core hopping method. PLoS One 2011; 6(11) e28111
[] [PMID: 22140516]

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Published on: 23 May, 2020
Page: [260 - 267]
Pages: 8
DOI: 10.2174/1574893614666191212112026
Price: $65

Article Metrics

PDF: 21
PRC: 1