A Network of Conserved Synthetic Lethal Interactions for Exploration of Precision Cancer Therapy

Rohith Srivas; John Paul Shen; Chih Cheng Yang; Su Ming Sun; Jianfeng Li; Andrew M Gross; James Jensen; Katherine Licon; Ana Bojorquez-Gomez; Kristin Klepper; Justin Huang; Daniel Pekin; Jia L Xu; Huwate Yeerna; Vignesh Sivaganesh; Leonie Kollenstart; Haico van Attikum; Pedro Aza-Blanc; Robert W Sobol; Trey Ideker

doi:10.1016/j.molcel.2016.06.022

A Network of Conserved Synthetic Lethal Interactions for Exploration of Precision Cancer Therapy

Mol Cell. 2016 Aug 4;63(3):514-25. doi: 10.1016/j.molcel.2016.06.022. Epub 2016 Jul 21.

Authors

Rohith Srivas¹, John Paul Shen², Chih Cheng Yang³, Su Ming Sun⁴, Jianfeng Li⁵, Andrew M Gross⁶, James Jensen⁶, Katherine Licon⁷, Ana Bojorquez-Gomez⁸, Kristin Klepper⁹, Justin Huang⁶, Daniel Pekin⁹, Jia L Xu⁹, Huwate Yeerna⁹, Vignesh Sivaganesh⁹, Leonie Kollenstart⁴, Haico van Attikum⁴, Pedro Aza-Blanc³, Robert W Sobol⁵, Trey Ideker¹⁰

Affiliations

¹ 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.
² 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.
³ Functional Genomics Core, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
⁴ Department of Human Genetics, Leiden University Medical Center, Einthovenweg 20, 2333 ZC, Leiden, the Netherlands.
⁵ 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.
⁶ Bioinformatics and Systems Biology Program, University of California, San Diego, La Jolla, CA 92093, USA.
⁷ 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.
⁸ Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA.
⁹ Division of Genetics, Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
¹⁰ 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.

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.

MeSH terms

Antineoplastic Agents / therapeutic use*
Biomarkers, Tumor / genetics*
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Female
Gene Expression Regulation, Fungal / drug effects
Gene Expression Regulation, Neoplastic / drug effects
Gene Regulatory Networks / drug effects*
Genes, Tumor Suppressor*
Genetic Predisposition to Disease
HeLa Cells
Humans
Kaplan-Meier Estimate
Molecular Targeted Therapy
Mutation*
Phenotype
Precision Medicine / methods*
Protein Interaction Maps / drug effects*
RNA Interference
RecQ Helicases / genetics
RecQ Helicases / metabolism
Saccharomyces cerevisiae / drug effects*
Saccharomyces cerevisiae / genetics
Saccharomyces cerevisiae / metabolism
Saccharomyces cerevisiae Proteins / genetics
Saccharomyces cerevisiae Proteins / metabolism
Signal Transduction / drug effects
Synthetic Lethal Mutations
Time Factors
Transfection
Uterine Cervical Neoplasms / drug therapy*
Uterine Cervical Neoplasms / genetics
Uterine Cervical Neoplasms / metabolism
Uterine Cervical Neoplasms / mortality

Substances

Antineoplastic Agents
Biomarkers, Tumor
Cell Cycle Proteins
Rad17 protein, human
Saccharomyces cerevisiae Proteins
Bloom syndrome protein
RecQ Helicases

Abstract

MeSH terms

Substances

Grants and funding