title: A Network of Conserved Synthetic Lethal Interactions for Exploration of Precision Cancer Therapy.
abstract: An emerging therapeutic strategy for cancer is to induce selective lethality in a tumor by exploiting interactions between its driving mutations and specific drug targets. Here we use a multi-species approach to develop a resource of synthetic lethal interactions relevant to cancer therapy. First, we screen in yeast ∼169,000 potential interactions among orthologs of human tumor suppressor genes (TSG) and genes encoding drug targets across multiple genotoxic environments. Guided by the strongest signal, we evaluate thousands of TSG-drug combinations in HeLa cells, resulting in networks of conserved synthetic lethal interactions. Analysis of these networks reveals that interaction stability across environments and shared gene function increase the likelihood of observing an interaction in human cancer cells. Using these rules, we prioritize ∼10(5) human TSG-drug combinations for future follow-up. We validate interactions based on cell and/or patient survival, including topoisomerases with RAD17 and checkpoint kinases with BLM.
authors.affiliation: Division of Genetics, Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA; The Cancer Cell Map Initiative.
authors.forename: Rohith
authors.initials: R
authors.lastname: Srivas
authors.affiliation: Division of Genetics, Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA; The Cancer Cell Map Initiative.
authors.forename: John Paul
authors.initials: JP
authors.lastname: Shen
authors.affiliation: Functional Genomics Core, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Chih Cheng
authors.initials: CC
authors.lastname: Yang
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Einthovenweg 20, 2333 ZC, Leiden, the Netherlands.
authors.forename: Su Ming
authors.initials: SM
authors.lastname: Sun
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Li
authors.affiliation: Bioinformatics and Systems Biology Program, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Gross
authors.affiliation: Bioinformatics and Systems Biology Program, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: James
authors.initials: J
authors.lastname: Jensen
authors.affiliation: Division of Genetics, Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Licon
authors.affiliation: Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Ana
authors.initials: A
authors.lastname: Bojorquez-Gomez
authors.affiliation: Division of Genetics, Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Kristin
authors.initials: K
authors.lastname: Klepper
authors.affiliation: Bioinformatics and Systems Biology Program, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Huang
authors.affiliation: Division of Genetics, Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Pekin
authors.affiliation: Division of Genetics, Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Jia L
authors.initials: JL
authors.lastname: Xu
authors.affiliation: Division of Genetics, Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Huwate
authors.initials: H
authors.lastname: Yeerna
authors.affiliation: Division of Genetics, Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Vignesh
authors.initials: V
authors.lastname: Sivaganesh
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Einthovenweg 20, 2333 ZC, Leiden, the Netherlands.
authors.forename: Leonie
authors.initials: L
authors.lastname: Kollenstart
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Einthovenweg 20, 2333 ZC, Leiden, the Netherlands.
authors.forename: Haico
authors.initials: H
authors.lastname: van Attikum
authors.affiliation: Functional Genomics Core, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Pedro
authors.initials: P
authors.lastname: Aza-Blanc
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Sobol
authors.affiliation: Division of Genetics, Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA; The Cancer Cell Map Initiative. Electronic address: tideker@ucsd.edu.
authors.forename: Trey
authors.initials: T
authors.lastname: Ideker
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000187:drug effects*; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D006367:HeLa Cells; D006801:Humans; D053208:Kaplan-Meier Estimate; D058990:Molecular Targeted Therapy; D009154:Mutation; D010641:Phenotype; D057285:Precision Medicine / Q000379:methods*; D060066:Protein Interaction Maps / Q000187:drug effects*; D034622:RNA Interference; D053484:RecQ Helicases / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000072020:Synthetic Lethal Mutations; D013997:Time Factors; D014162:Transfection; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; C113575:Rad17 protein, human; D029701:Saccharomyces cerevisiae Proteins; C097151:Bloom syndrome protein; D053484:RecQ Helicases