학술논문
A comprehensive clinically informed map of dependencies in cancer cells and framework for target prioritization.
Document Type
Academic Journal
Author
Pacini C; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK; Open Targets, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK.; Duncan E; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK; Open Targets, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK.; Gonçalves E; Instituto Superior Técnico (IST), Universidade de Lisboa, 1049-001 Lisboa, Portugal; INESC-ID, 1000-029 Lisboa, Portugal.; Gilbert J; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK.; Bhosle S; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK.; Horswell S; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK; Open Targets, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK.; Karakoc E; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK; Open Targets, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK.; Lightfoot H; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK.; Curry E; Genome Biology, Genomic Sciences, GSK, Stevenage, UK.; Muyas F; European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, Cambridge CB10 1SD, UK.; Bouaboula M; Sanofi Research and Development, Cambridge, MA, USA.; Pedamallu CS; Sanofi Research and Development, Cambridge, MA, USA.; Cortes-Ciriano I; European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, Cambridge CB10 1SD, UK.; Behan FM; Genome Biology, Genomic Sciences, GSK, Stevenage, UK.; Zalmas LP; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK; Open Targets, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK.; Barthorpe A; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK.; Francies H; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK; Genome Biology, Genomic Sciences, GSK, Stevenage, UK.; Rowley S; Sanofi Research and Development, Cambridge, MA, USA.; Pollard J; Sanofi Research and Development, Cambridge, MA, USA.; Beltrao P; Open Targets, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK; European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, Cambridge CB10 1SD, UK.; Parts L; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK; Open Targets, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK.; Iorio F; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK; Open Targets, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK; Human Technopole, V.le Rita Levi-Montalcini, 1, 20157 Milano, Italy. Electronic address: francesco.iorio@fht.org.; Garnett MJ; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK; Open Targets, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK. Electronic address: mg12@sanger.ac.uk.
Source
Publisher: Cell Press Country of Publication: United States NLM ID: 101130617 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1878-3686 (Electronic) Linking ISSN: 15356108 NLM ISO Abbreviation: Cancer Cell Subsets: MEDLINE
Subject
Language
English
Abstract
Genetic screens in cancer cell lines inform gene function and drug discovery. More comprehensive screen datasets with multi-omics data are needed to enhance opportunities to functionally map genetic vulnerabilities. Here, we construct a second-generation map of cancer dependencies by annotating 930 cancer cell lines with multi-omic data and analyze relationships between molecular markers and cancer dependencies derived from CRISPR-Cas9 screens. We identify dependency-associated gene expression markers beyond driver genes, and observe many gene addiction relationships driven by gain of function rather than synthetic lethal effects. By combining clinically informed dependency-marker associations with protein-protein interaction networks, we identify 370 anti-cancer priority targets for 27 cancer types, many of which have network-based evidence of a functional link with a marker in a cancer type. Mapping these targets to sequenced tumor cohorts identifies tractable targets in different cancer types. This target prioritization map enhances understanding of gene dependencies and identifies candidate anti-cancer targets for drug development.
Competing Interests: Declaration of interests This study was funded by Open Targets, a public-private initiative involving academia and industry. M.J.G. receives funding from AstraZeneca, GlaxoSmithKline, and Astex Pharmaceuticals. F.I. receives funding from Nerviano Medical Sciences S.r.l and performs consultancy for the Cancer Research Horizons-AstraZeneca Functional Genomics Center and for Mosaic Therapeutics. M.J.G. is a founder, has equity in and is a consultant for Mosaic Therapeutics.
(Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Competing Interests: Declaration of interests This study was funded by Open Targets, a public-private initiative involving academia and industry. M.J.G. receives funding from AstraZeneca, GlaxoSmithKline, and Astex Pharmaceuticals. F.I. receives funding from Nerviano Medical Sciences S.r.l and performs consultancy for the Cancer Research Horizons-AstraZeneca Functional Genomics Center and for Mosaic Therapeutics. M.J.G. is a founder, has equity in and is a consultant for Mosaic Therapeutics.
(Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)