ArticleBioinformatics (Oxford, England)2014
Bioinformatics-driven discovery of rational combination for overcoming EGFR-mutant lung cancer resistance to EGFR therapy.
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Article in Bioinformatics (Oxford, England), 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14citing papers in PubMed
3.1field-weighted citation impact, top 8% of its field
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14 citing papers in PubMed, 25 citations in OpenAlex.
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Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
14 authors at 3 institutions in 1 country.
Jihye KimDivision 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.
Vihas T VasuDivision 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.
Rangnath MishraDivision 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.
Katherine R SingletonDivision 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.
Minjae YooDivision 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.
Sonia M LeachDivision 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.
Eveline Farias-HessonDivision 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.
Robert J MasonDivision 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.
Jaewoo KangDivision 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.
Preveen RamamoorthyDivision 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.
Jeffrey A KernDivision 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.
Lynn E HeasleyDivision 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.
James H FiniganDivision 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.
Aik Choon TanDivision 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.
National Jewish Health · USUniversity of Colorado Anschutz Medical Campus · USUniversity of Colorado Denver · US
Funding
University of Colorado Cancer Center Support Grant - Lung Cancer Patient-Derived Xenografts with Autologous Human Immune SystemsP30CA046934 · NCI · UNIVERSITY OF COLORADO DENVER · PI James V Degregori · 1988 to 2026
$117.0MTissue Bank and Biomarkers CoreP50CA058187 · NCI · UNIVERSITY OF COLORADO DENVER · PI MILLER, YORK E · 1992 to 2018
$43.8MADAM17-NRG-1 Signaling in Acute Lung InjuryR01HL111674 · NHLBI · NATIONAL JEWISH HEALTH · PI FINIGAN, JAMES H · 2012 to 2016
$1.9MFGF-2 Autocrine Signaling in Lung CancerR01CA127105 · NCI · UNIVERSITY OF COLORADO DENVER · PI HEASLEY, LYNN E · 2008 to 2012
$1.6MAir/liquid interface cultures for alveolar type II cell differentiationR21HL106112 · NHLBI · NATIONAL JEWISH HEALTH · PI MASON, ROBERT JAMES · 2011 to 2012
$436kNCI NIH HHS P30 CA046934NCI NIH HHS P30CA046934NCI NIH HHS P50 CA058187NCI NIH HHS P50CA58187NCI NIH HHS R01 CA127105NCI NIH HHS R01CA127105NHLBI NIH HHS R01HL106112NHLBI NIH HHS R01 HL111674NHLBI NIH HHS R01HL111674NHLBI NIH HHS R21 HL106112
Abstract
motivationNon-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.
resultWe 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.
conclusionsWe 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. AVAILABILITY AND IMPLEMENTATION: K-Map can be accessible at: http://tanlab.ucdenver.edu/kMap. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Indexed as
Aniline CompoundsAntineoplastic Combined Chemotherapy ProtocolsCarcinoma, Non-Small-Cell LungCell Line, TumorComputational BiologyDrug Resistance, NeoplasmErbB ReceptorsGefitinibHumansLung NeoplasmsMutationNitrilesProtein Kinase InhibitorsProtein KinasesQuinazolinesQuinolinesAniline CompoundsbosutinibErbB ReceptorsGefitinibNitrilesProtein Kinase InhibitorsProtein KinasesQuinazolinesQuinolines
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.