title: Prediction of individualized therapeutic vulnerabilities in cancer from genomic profiles.
abstract: BACKGROUND
  Somatic homozygous deletions of chromosomal regions in cancer, while not necessarily oncogenic, may lead to therapeutic vulnerabilities specific to cancer cells compared with normal cells. A recently reported example is the loss of one of the two isoenzymes in glioblastoma cancer cells such that the use of a specific inhibitor selectively inhibited growth of the cancer cells, which had become fully dependent on the second isoenzyme. We have now made use of the unprecedented conjunction of large-scale cancer genomics profiling of tumor samples in The Cancer Genome Atlas (TCGA) and of tumor-derived cell lines in the Cancer Cell Line Encyclopedia, as well as the availability of integrated pathway information systems, such as Pathway Commons, to systematically search for a comprehensive set of such epistatic vulnerabilities.
  
  
  RESULTS
  Based on homozygous deletions affecting metabolic enzymes in 16 TCGA cancer studies and 972 cancer cell lines, we identified 4104 candidate metabolic vulnerabilities present in 1019 tumor samples and 482 cell lines. Up to 44% of these vulnerabilities can be targeted with at least one Food and Drug Administration-approved drug. We suggest focused experiments to test these vulnerabilities and clinical trials based on personalized genomic profiles of those that pass preclinical filters. We conclude that genomic profiling will in the future provide a promising basis for network pharmacology of epistatic vulnerabilities as a promising therapeutic strategy.
  
  
  METHODS
  A web-based tool for exploring all vulnerabilities and their details is available at http://cbio.mskcc.org/cancergenomics/statius/ along with supplemental data files.
authors.affiliation: Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065 and Tri-Institutional Training Program in Computational Biology & Medicine, New York, NY 10065, USAComputational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065 and Tri-Institutional Training Program in Computational Biology & Medicine, New York, NY 10065, USA.
authors.forename: Bülent Arman
authors.initials: BA
authors.lastname: Aksoy
authors.affiliation: Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065 and Tri-Institutional Training Program in Computational Biology & Medicine, New York, NY 10065, USA.
authors.forename: Emek
authors.initials: E
authors.lastname: Demir
authors.affiliation: Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065 and Tri-Institutional Training Program in Computational Biology & Medicine, New York, NY 10065, USA.
authors.forename: Özgün
authors.initials: Ö
authors.lastname: Babur
authors.affiliation: Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065 and Tri-Institutional Training Program in Computational Biology & Medicine, New York, NY 10065, USA.
authors.forename: Weiqing
authors.initials: W
authors.lastname: Wang
authors.affiliation: Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065 and Tri-Institutional Training Program in Computational Biology & Medicine, New York, NY 10065, USA.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Jing
authors.affiliation: Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065 and Tri-Institutional Training Program in Computational Biology & Medicine, New York, NY 10065, USA.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Schultz
authors.affiliation: Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065 and Tri-Institutional Training Program in Computational Biology & Medicine, New York, NY 10065, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Sander
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D056915:DNA Copy Number Variations; D017353:Gene Deletion; D023281:Genomics / Q000379:methods*; D005909:Glioblastoma / Q000235:genetics; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics*; D057285:Precision Medicine
chemical_list: D007527:Isoenzymes