al . - Mutant Lung Cancer LKB 1 Deoxythymidylate Kinase as a Target in Metabolic and Functional Genomic Studies Identify

The LKB1/STK11 tumor suppressor encodes a serine/threonine kinase, which coordinates cell growth, polarity, motility, and metabolism. In non–small cell lung carcinoma, LKB1 is somatically inactivated in 25% to 30% of cases, often concurrently with activating KRAS mutations. Here, we used an integrative approach to defi ne novel therapeutic targets in KRAS-driven LKB1 -mutant lung cancers. High-throughput RNA interference screens in lung cancer cell lines from genetically engineered mouse models driven by activated KRAS with or without coincident Lkb1 deletion led to the identifi cation of Dtymk , encoding deoxythymidylate kinase (DTYMK), which catalyzes dTTP biosynthesis, as synthetically lethal with Lkb1 defi ciency in mouse and human lung cancer lines. Global metabolite profi ling showed that Lkb1null cells had a striking decrease in multiple nucleotide metabolites as compared with the Lkb1 –wild-type cells. Thus, LKB1 -mutant lung cancers have defi cits in nucleotide metabolism that confer hypersensitivity to DTYMK inhibition, suggesting that DTYMK is a potential therapeutic target in this aggressive subset of tumors. SIGNIFICANCE: Using cell lines derived from the lung cancers occurring in genetically engineered mice, we conducted an integrative genome-wide short hairpin RNA and metabolite screen to identify DTYMK as a potential therapeutic target in Kras/Lkb1 –mutant lung cancer. We believe that DTYMK is tractable for the development of novel therapeutics, and show an integrative approach to target identifi cation that reduces false-positive candidates and should have broad applicability for the development of targeted therapeutics. Cancer Discov; 3(8); 870–9. ©2013 AACR. See related commentary by Marcus and Khuri, p. 843. Authors’ Affiliations: Departments of 1 Medicine, 2 Biological Chemistry and Molecular Pharmacology, and 3 Radiation Oncology; 4 Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School; 5 Department of Medical Oncology; 6 Lowe Center for Thoracic Oncology; 7 Ludwig Center, Dana-Farber/Harvard Cancer Center; 8 Massachusetts General Hospital Cancer Center; 9 Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston; 10 Agios Pharmaceuticals; 11 Broad Institute of MIT and Harvard, Cambridge, Massachusetts; 12 Lineberger Comprehensive Cancer Center; 13 Department of Medicine and Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; 14 Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California; 15 The University of Texas MD Anderson Cancer Center, Houston, Texas; 16 Department of Pediatrics, Columbia University Medical Center, New York, New York; 17 Department of Physiology, University of Valencia, Burjassot, Spain Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/). Corresponding Author: Kwok-Kin Wong, Dana-Farber Cancer Institute, Dana Building 810B, 450 Brookline Avenue, HIM243, Boston, MA 02115. Phone: 617-632-6084; Fax: 617-632-7839; E-mail: [email protected] doi: 10.1158/2159-8290.CD-13-0015 ©2013 American Association for Cancer Research. Metabolic and Functional Genomic Studies Identify Deoxythymidylate Kinase as a Target in LKB1 -Mutant Lung Cancer Yan Liu 1 , 5 , 6 , 7 , Kevin Marks 10 , Glenn S. Cowley 11 , Julian Carretero 17 , Qingsong Liu 2 , Thomas J.F. Nieland 11 , Chunxiao Xu 1 , 5 , 6 , 7 , Travis J. Cohoon 1 , 5 , 6 , 7 , Peng Gao 1 , 5 , 6 , 7 , Yong Zhang 1 , 5 , Zhao Chen 1 , 5 , 6 , 7 , Abigail B. Altabef 1 , 5 , 6 , 7 , Jeremy H. Tchaicha 1 , 5 , 6 , 7 , Xiaoxu Wang 1 , 3 , Sung Choe 10 , Edward M. Driggers 10 , Jianming Zhang 2 , Sean T. Bailey 12 , 13 , Norman E. Sharpless 12 , 13 , D. Neil Hayes 12 , 13 , Nirali M. Patel 12 , 13 , Pasi A. Janne 1 , 5 , 6 , Nabeel Bardeesy 1 , 8 , Jeffrey A. Engelman 1 , 8 , Brendan D. Manning 9 , Reuben J. Shaw 14 , John M. Asara 4 , Ralph Scully 14 , Alec Kimmelman 1 , 3 , Lauren A. Byers 15 , Don L. Gibbons 15 , Ignacio I. Wistuba 15 , John V. Heymach 15 , David J. Kwiatkowski 1 , 5 , 6 , William Y. Kim 12 , 13 , Andrew L. Kung 16 , Nathanael S. Gray 2 , David E. Root 11 , Lewis C. Cantley 4 , and Kwok-Kin Wong 1,5,6,7 on May 23, 2014. © 2013 American Association for Cancer Research. cancerdiscovery.aacrjournals.org Downloaded from Published OnlineFirst May 28, 2013; DOI: 10.1158/2159-8290.CD-13-0015