title: Bioinformatics-driven discovery of rational combination for overcoming EGFR-mutant lung cancer resistance to EGFR therapy.
abstract: BACKGROUND
  Non-small-cell lung cancer (NSCLC) is the leading cause of cancer death in the United States. Targeted tyrosine kinase inhibitors (TKIs) directed against the epidermal growth factor receptor (EGFR) have been widely and successfully used in treating NSCLC patients with activating EGFR mutations. Unfortunately, the duration of response is short-lived, and all patients eventually relapse by acquiring resistance mechanisms.
  
  
  RESULTS
  We performed an integrative systems biology approach to determine essential kinases that drive EGFR-TKI resistance in cancer cell lines. We used a series of bioinformatics methods to analyze and integrate the functional genetics screen and RNA-seq data to identify a set of kinases that are critical in survival and proliferation in these TKI-resistant lines. By connecting the essential kinases to compounds using a novel kinase connectivity map (K-Map), we identified and validated bosutinib as an effective compound that could inhibit proliferation and induce apoptosis in TKI-resistant lines. A rational combination of bosutinib and gefitinib showed additive and synergistic effects in cancer cell lines resistant to EGFR TKI alone.
  
  
  CONCLUSIONS
  We have demonstrated a bioinformatics-driven discovery roadmap for drug repurposing and development in overcoming resistance in EGFR-mutant NSCLC, which could be generalized to other cancer types in the era of personalized medicine.
  
  
  METHODS
  K-Map can be accessible at: http://tanlab.ucdenver.edu/kMap.
  
  
  BACKGROUND
  Supplementary data are available at Bioinformatics online.
authors.affiliation: Division of Medical Oncology, Department of Medicine, Translational Bioinformatics and Cancer Systems Biology Laboratory, University of Colorado Anschutz Medical Campus, 80045 Aurora, Department of Medicine, National Jewish Health, 80206 Denver, Department of Craniofacial Biology, School of Dental Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, 80045 Aurora, CO, USA and Department of Computer Science and Engineering, Korea University, Seoul 136-713, Korea.
authors.forename: Jihye
authors.initials: J
authors.lastname: Kim
authors.affiliation: Division of Medical Oncology, Department of Medicine, Translational Bioinformatics and Cancer Systems Biology Laboratory, University of Colorado Anschutz Medical Campus, 80045 Aurora, Department of Medicine, National Jewish Health, 80206 Denver, Department of Craniofacial Biology, School of Dental Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, 80045 Aurora, CO, USA and Department of Computer Science and Engineering, Korea University, Seoul 136-713, Korea.
authors.forename: Vihas T
authors.initials: VT
authors.lastname: Vasu
authors.affiliation: Division of Medical Oncology, Department of Medicine, Translational Bioinformatics and Cancer Systems Biology Laboratory, University of Colorado Anschutz Medical Campus, 80045 Aurora, Department of Medicine, National Jewish Health, 80206 Denver, Department of Craniofacial Biology, School of Dental Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, 80045 Aurora, CO, USA and Department of Computer Science and Engineering, Korea University, Seoul 136-713, Korea.
authors.forename: Rangnath
authors.initials: R
authors.lastname: Mishra
authors.affiliation: Division of Medical Oncology, Department of Medicine, Translational Bioinformatics and Cancer Systems Biology Laboratory, University of Colorado Anschutz Medical Campus, 80045 Aurora, Department of Medicine, National Jewish Health, 80206 Denver, Department of Craniofacial Biology, School of Dental Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, 80045 Aurora, CO, USA and Department of Computer Science and Engineering, Korea University, Seoul 136-713, Korea.
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Singleton
authors.affiliation: Division of Medical Oncology, Department of Medicine, Translational Bioinformatics and Cancer Systems Biology Laboratory, University of Colorado Anschutz Medical Campus, 80045 Aurora, Department of Medicine, National Jewish Health, 80206 Denver, Department of Craniofacial Biology, School of Dental Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, 80045 Aurora, CO, USA and Department of Computer Science and Engineering, Korea University, Seoul 136-713, Korea.
authors.forename: Minjae
authors.initials: M
authors.lastname: Yoo
authors.affiliation: Division of Medical Oncology, Department of Medicine, Translational Bioinformatics and Cancer Systems Biology Laboratory, University of Colorado Anschutz Medical Campus, 80045 Aurora, Department of Medicine, National Jewish Health, 80206 Denver, Department of Craniofacial Biology, School of Dental Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, 80045 Aurora, CO, USA and Department of Computer Science and Engineering, Korea University, Seoul 136-713, Korea.
authors.forename: Sonia M
authors.initials: SM
authors.lastname: Leach
authors.affiliation: Division of Medical Oncology, Department of Medicine, Translational Bioinformatics and Cancer Systems Biology Laboratory, University of Colorado Anschutz Medical Campus, 80045 Aurora, Department of Medicine, National Jewish Health, 80206 Denver, Department of Craniofacial Biology, School of Dental Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, 80045 Aurora, CO, USA and Department of Computer Science and Engineering, Korea University, Seoul 136-713, Korea.
authors.forename: Eveline
authors.initials: E
authors.lastname: Farias-Hesson
authors.affiliation: Division of Medical Oncology, Department of Medicine, Translational Bioinformatics and Cancer Systems Biology Laboratory, University of Colorado Anschutz Medical Campus, 80045 Aurora, Department of Medicine, National Jewish Health, 80206 Denver, Department of Craniofacial Biology, School of Dental Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, 80045 Aurora, CO, USA and Department of Computer Science and Engineering, Korea University, Seoul 136-713, Korea Division of Medical Oncology, Department of Medicine, Translational Bioinformatics and Cancer Systems Biology Laboratory, University of Colorado Anschutz Medical Campus, 80045 Aurora, Department of Medicine, National Jewish Health, 80206 Denver, Department of Craniofacial Biology, School of Dental Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, 80045 Aurora, CO, USA and Department of Computer Science and Engineering, Korea University, Seoul 136-713, Korea.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mason
authors.affiliation: Division of Medical Oncology, Department of Medicine, Translational Bioinformatics and Cancer Systems Biology Laboratory, University of Colorado Anschutz Medical Campus, 80045 Aurora, Department of Medicine, National Jewish Health, 80206 Denver, Department of Craniofacial Biology, School of Dental Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, 80045 Aurora, CO, USA and Department of Computer Science and Engineering, Korea University, Seoul 136-713, Korea.
authors.forename: Jaewoo
authors.initials: J
authors.lastname: Kang
authors.affiliation: Division of Medical Oncology, Department of Medicine, Translational Bioinformatics and Cancer Systems Biology Laboratory, University of Colorado Anschutz Medical Campus, 80045 Aurora, Department of Medicine, National Jewish Health, 80206 Denver, Department of Craniofacial Biology, School of Dental Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, 80045 Aurora, CO, USA and Department of Computer Science and Engineering, Korea University, Seoul 136-713, Korea.
authors.forename: Preveen
authors.initials: P
authors.lastname: Ramamoorthy
authors.affiliation: Division of Medical Oncology, Department of Medicine, Translational Bioinformatics and Cancer Systems Biology Laboratory, University of Colorado Anschutz Medical Campus, 80045 Aurora, Department of Medicine, National Jewish Health, 80206 Denver, Department of Craniofacial Biology, School of Dental Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, 80045 Aurora, CO, USA and Department of Computer Science and Engineering, Korea University, Seoul 136-713, Korea Division of Medical Oncology, Department of Medicine, Translational Bioinformatics and Cancer Systems Biology Laboratory, University of Colorado Anschutz Medical Campus, 80045 Aurora, Department of Medicine, National Jewish Health, 80206 Denver, Department of Craniofacial Biology, School of Dental Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, 80045 Aurora, CO, USA and Department of Computer Science and Engineering, Korea University, Seoul 136-713, Korea.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Kern
authors.affiliation: Division of Medical Oncology, Department of Medicine, Translational Bioinformatics and Cancer Systems Biology Laboratory, University of Colorado Anschutz Medical Campus, 80045 Aurora, Department of Medicine, National Jewish Health, 80206 Denver, Department of Craniofacial Biology, School of Dental Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, 80045 Aurora, CO, USA and Department of Computer Science and Engineering, Korea University, Seoul 136-713, Korea.
authors.forename: Lynn E
authors.initials: LE
authors.lastname: Heasley
authors.affiliation: Division of Medical Oncology, Department of Medicine, Translational Bioinformatics and Cancer Systems Biology Laboratory, University of Colorado Anschutz Medical Campus, 80045 Aurora, Department of Medicine, National Jewish Health, 80206 Denver, Department of Craniofacial Biology, School of Dental Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, 80045 Aurora, CO, USA and Department of Computer Science and Engineering, Korea University, Seoul 136-713, Korea Division of Medical Oncology, Department of Medicine, Translational Bioinformatics and Cancer Systems Biology Laboratory, University of Colorado Anschutz Medical Campus, 80045 Aurora, Department of Medicine, National Jewish Health, 80206 Denver, Department of Craniofacial Biology, School of Dental Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, 80045 Aurora, CO, USA and Department of Computer Science and Engineering, Korea University, Seoul 136-713, Korea.
authors.forename: James H
authors.initials: JH
authors.lastname: Finigan
authors.affiliation: Division of Medical Oncology, Department of Medicine, Translational Bioinformatics and Cancer Systems Biology Laboratory, University of Colorado Anschutz Medical Campus, 80045 Aurora, Department of Medicine, National Jewish Health, 80206 Denver, Department of Craniofacial Biology, School of Dental Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, 80045 Aurora, CO, USA and Department of Computer Science and Engineering, Korea University, Seoul 136-713, Korea Division of Medical Oncology, Department of Medicine, Translational Bioinformatics and Cancer Systems Biology Laboratory, University of Colorado Anschutz Medical Campus, 80045 Aurora, Department of Medicine, National Jewish Health, 80206 Denver, Department of Craniofacial Biology, School of Dental Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, 80045 Aurora, CO, USA and Department of Computer Science and Engineering, Korea University, Seoul 136-713, Korea.
authors.forename: Aik Choon
authors.initials: AC
authors.lastname: Tan
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics*; D045744:Cell Line, Tumor; D019295:Computational Biology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics*; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D009154:Mutation; D009570:Nitriles / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011494:Protein Kinases / Q000235:genetics; D011799:Quinazolines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D017423:Sequence Analysis, RNA
chemical_list: D000814:Aniline Compounds; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D011804:Quinolines; C471992:bosutinib; D011494:Protein Kinases; D066246:ErbB Receptors; D000077156:Gefitinib