Metabolic and functional genomic studies identify deoxythymidylate kinase as a target in LKB1 -mutant lung cancer

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 Lkb1- null 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.