RESEARCH ARTICLE for clinical develo ent of WRN antas s an adiunc 20K b.A S.We P.Waite.M.Adman,E T.Loeb.LA The therapy to approve that effe h as WRN.Efforts in t 052o0 ch as ne hu text-specific dependences as part ormative to improve suc Nucleic Acids Res. Online content 25 5(2009 tp//doi.org/10.103 /s41586 019-1103- arch 01. cy.N Eng 27.Ts map.Cel1764-7 D.Adams.G. and L.Parts to ust grant 20619Y a,H.LI,Y.lan,E-P.Del UD g 32267-273201 A ived the project.F.M.B nd ve ape of pha cancer.Cell 166 ses and ngu v.ca ed ou and contribu dto in v expe 2016 ed by lar restsEAS.D.D.CB.-D.RS.andYR try.K.Y 02016. .KK a practica m9 2n9cdnrgm59bietorhspaperathips/aoiorg10.1038ys415gG 103.9 tion is available at http://ww spondence and requests for materials should be addressed to K.Y.or 200 The Author(s).under exclusive licence to Springer Nature Limited 2019RESEARCH Article for clinical development of WRN antagonists would be as an adjunct therapy to approved immune checkpoint inhibitors in MSI tumours26. In summary, we developed an unbiased and systematic framework that effectively ranks priority targets, such as WRN. Efforts such as ours, and from others5,8,12,22,27,28, to build a compendium of fitness genes, and the identification of context-specific dependencies as part of a cancer dependency map, could be transformative to improve suc￾cess rates in the development of cancer drugs. Online content Any methods, additional references, Nature Research reporting summaries, source data, statements of data availability and associated accession codes are available at https://doi.org/10.1038/s41586-019-1103-9. Received: 3 August 2018; Accepted: 8 March 2019; Published online xx xx xxxx. 1. Garraway, L. A. Genomics-driven oncology: framework for an emerging paradigm. J. Clin. Oncol. 31, 1806–1814 (2013). 2. Zehir, A. et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat. Med. 23, 703–713 (2017). 3. Hay, M., Thomas, D. W., Craighead, J. L., Economides, C. & Rosenthal, J. Clinical development success rates for investigational drugs. Nat. 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Gene essentiality profling reveals gene networks and synthetic lethal interactions with oncogenic Ras. Cell 168, 890–903 (2017). Acknowledgements We thank D. Adams, G. Vassiliou and L. Parts for comments on the manuscript, members of the M.J.G. laboratory and Sanger Institute facilities (Wellcome Trust grant 206194). Work was funded by Open Targets (OTAR015) to M.J.G., K.Y. and J.S.-R. The K.Y. laboratory is supported by Wellcome Trust (206194). The M.J.G. laboratory is supported by SU2C (SU2C￾AACR-DT1213) and Wellcome Trust (102696 and 206194). Support was also received from AIRC 20697 (A.B.) and 18532 (L.T.); 5x1000 grant 21091 (A.B. and L.T.); ERC Consolidator Grant 724748 – BEAT (A.B.); FPRC-ONLUS, 5x1000 Ministero della Salute 2011 and 2014 (L.T.); and Transcan, TACTIC (L.T.). Author contributions M.J.G., K.Y. and C.B.-D. conceived the project. F.M.B. led CRISPR–Cas9 screening, co-developed the project Score web portal, contributed to analysis strategy, performed validation analyses and verified WRN dependency. F.I. led computational analyses and figure preparation, and contributed to the project Score web portal. G.P. performed experiments to verify WRN dependency, carried out analyses and contributed to in vivo studies. E.G. contributed to computational analysis and figure preparation. D.v.d.M. contributed to the project Score web portal. G.M., F.S., M.P., A.B. and L.T. performed in vivo studies. C.M.B., R.A., D.A.J., R.M., R.P. and P.W. performed CRISPR–Cas9 screens. R.S. performed tractability analysis. Y.R. performed WRN rescue experiments. C.M.B., S.H., A.B., L.T., E.A.S., D.D. and J.S.-R. assisted with project supervision. F.M.B., F.I., E.G., G.P., K.Y. and M.J.G. wrote the manuscript. K.Y. and M.J.G. directed the project. J.S.-R., A.B., L.T., M.J.G. and K.Y. acquired funding. All authors approved the manuscript. Competing interests E.A.S., D.D., C.B.-D., R.S. and Y.R. are GlaxoSmithKline employees. Open Targets is a public–private initiative involving academia and industry. K.Y. and M.J.G. receive funding from AstraZeneca. M.J.G. performed consultancy for Sanofi. All other authors declare no competing interests. Additional information Extended data is available for this paper at https://doi.org/10.1038/s41586- 019-1103-9. Supplementary information is available for this paper at https://doi.org/ 10.1038/s41586-019-1103-9. Reprints and permissions information is available at http://www.nature.com/ reprints. Correspondence and requests for materials should be addressed to K.Y. or M.J.G. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. © The Author(s), under exclusive licence to Springer Nature Limited 2019 N A t U r e | www.nature.com/nature