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Metabolic and Functional Genomic Studies Identify Deoxythymidylate Kinase as a Target in LKB1 -Mutant Lung Cancer

2013; American Association for Cancer Research; Volume: 3; Issue: 8 Linguagem: Inglês

10.1158/2159-8290.cd-13-0015

2159-8290

Yan Liu, Kevin Marks, Glenn S. Cowley, Julián Carretero, Qingsong Liu, Thomas J.F. Nieland, Chunxiao Xu, Travis J. Cohoon, Peng Gao, Yong Zhang, Zhao Chen, Abigail B. Altabef, Jeremy H. Tchaicha, Xiaoxu Wang, Sung Choe, Edward M. Driggers, Jianming Zhang, Sean T. Bailey, Norman E. Sharpless, D. Neil Hayes, Nirali M. Patel, Pasi A. Jänne, Nabeel Bardeesy, Jeffrey A. Engelman, Brendan D. Manning, Reuben J. Shaw, John M. Asara, Ralph Scully, Alec C. Kimmelman, Lauren A. Byers, Don L. Gibbons, Ignacio I. Wistuba, John V. Heymach, David J. Kwiatkowski, William Y. Kim, Andrew L. Kung, Nathanael S. Gray, David E. Root, Lewis C. Cantley, Kwok‐Kin Wong,

Lung Cancer Treatments and Mutations

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 define 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 identification of Dtymk, encoding deoxythymidylate kinase (DTYMK), which catalyzes dTTP biosynthesis, as synthetically lethal with Lkb1 deficiency in mouse and human lung cancer lines. Global metabolite profiling 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 deficits in nucleotide metabolism that confer hypersensitivity to DTYMK inhibition, suggesting that DTYMK is a potential therapeutic target in this aggressive subset of tumors.