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

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

Author information

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.

PMID:
27453043
PMCID:
PMC5209245
DOI:
10.1016/j.molcel.2016.06.022
[Indexed for MEDLINE]
Free PMC Article

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