Title: A Network of Conserved Synthetic Lethal Interactions for Exploration of Precision Cancer Therapy.
Authors: Srivas, Rohith; Shen, John Paul; Yang, Chih Cheng; Sun, Su Ming; Li, Jianfeng; Gross, Andrew M; Jensen, James; Licon, Katherine; Bojorquez-Gomez, Ana; Klepper, Kristin; Huang, Justin; Pekin, Daniel; Xu, Jia L; Yeerna, Huwate; Sivaganesh, Vignesh; Kollenstart, Leonie; van Attikum, Haico; Aza-Blanc, Pedro; Sobol, Robert W; Ideker, Trey
Published In Mol Cell, (2016 08 04)
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.
PubMed ID: 27453043
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 Proteins/genetics; Saccharomyces cerevisiae Proteins/metabolism; Saccharomyces cerevisiae/drug effects*; Saccharomyces cerevisiae/genetics; Saccharomyces cerevisiae/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