Personalized prediction of EGFR mutation-induced drug resistance in lung cancer
Open Access
- 4 October 2013
- journal article
- research article
- Published by Springer Nature in Scientific Reports
- Vol. 3 (1) , 2855
Abstract
EGFR mutation-induced drug resistance has significantly impaired the potency of small molecule tyrosine kinase inhibitors in lung cancer treatment. Computational approaches can provide powerful and efficient techniques in the investigation of drug resistance. In our work, the EGFR mutation feature is characterized by the energy components of binding free energy (concerning the mutant-inhibitor complex), and we combine it with specific personal features for 168 clinical subjects to construct a personalized drug resistance prediction model. The 3D structure of an EGFR mutant is computationally predicted from its protein sequence, after which the dynamics of the bound mutant-inhibitor complex is simulated via AMBER and the binding free energy of the complex is calculated based on the dynamics. The utilization of extreme learning machines and leave-one-out cross-validation promises a successful identification of resistant subjects with high accuracy. Overall, our study demonstrates advantages in the development of personalized medicine/therapy design and innovative drug discovery.Keywords
This publication has 39 references indexed in Scilit:
- Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancerNature Genetics, 2012
- Predicting drug resistance of the HIV‐1 protease using molecular interaction energy componentsProteins: Structure, Function, and Bioinformatics, 2008
- The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATPProceedings of the National Academy of Sciences, 2008
- Loop modeling: Sampling, filtering, and scoringProteins: Structure, Function, and Bioinformatics, 2008
- Editors' ReplyPLOS Medicine, 2005
- Acquired Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib Is Associated with a Second Mutation in the EGFR Kinase DomainPLOS Medicine, 2005
- UCSF Chimera—A visualization system for exploratory research and analysisJournal of Computational Chemistry, 2004
- Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non–Small-Cell Lung Cancer to GefitinibNew England Journal of Medicine, 2004
- Fast, efficient generation of high‐quality atomic charges. AM1‐BCC model: II. Parameterization and validationJournal of Computational Chemistry, 2002
- The Protein Data BankNucleic Acids Research, 2000