title: Computational discovery of pathway-level genetic vulnerabilities in non-small-cell lung cancer.
abstract: Novel approaches are needed for discovery of targeted therapies for non-small-cell lung cancer (NSCLC) that are specific to certain patients. Whole genome RNAi screening of lung cancer cell lines provides an ideal source for determining candidate drug targets.
  
  
  
  Unsupervised learning algorithms uncovered patterns of differential vulnerability across lung cancer cell lines to loss of functionally related genes. Such genetic vulnerabilities represent candidate targets for therapy and are found to be involved in splicing, translation and protein folding. In particular, many NSCLC cell lines were especially sensitive to the loss of components of the LSm2-8 protein complex or the CCT/TRiC chaperonin. Different vulnerabilities were also found for different cell line subgroups. Furthermore, the predicted vulnerability of a single adenocarcinoma cell line to loss of the Wnt pathway was experimentally validated with screening of small-molecule Wnt inhibitors against an extensive cell line panel.
  
  
  
  The clustering algorithm is implemented in Python and is freely available at https://bitbucket.org/youngjh/nsclc_paper
  
  
  
  marcotte@icmb.utexas.edu or jon.young@utexas.edu
  
  
  
  Supplementary data are available at Bioinformatics online.
authors.affiliation: Institute for Computational Engineering and Sciences, University of Texas at Austin, Austin, TX, USA, Center for Systems and Synthetic Biology and Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Young
authors.affiliation: Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Peyton
authors.affiliation: Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea, and.
authors.forename: Hyun
authors.initials: H
authors.lastname: Seok Kim
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: McMillan
authors.affiliation: Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: White
authors.affiliation: Institute for Computational Engineering and Sciences, University of Texas at Austin, Austin, TX, USA, Center for Systems and Synthetic Biology and Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA.
authors.forename: Edward M
authors.initials: EM
authors.lastname: Marcotte
mesh_terms: D000465:Algorithms; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D016000:Cluster Analysis; D004273:DNA, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*
chemical_list: D004273:DNA, Neoplasm