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

Abstract

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.

• Authors: Yan Liu, Kevin Marks, Glenn S Cowley, Julian 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 Janne, Nabeel Bardeesy, Jeffrey A Engelman, Brendan D Manning, Reuben J Shaw, John M Asara, Ralph Scully, Alec 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
• Journal: Cancer discovery (Cancer Discov) Vol. 3 Issue 8 Pg. 870-9 (Aug 2013) ISSN: 2159-8290 [Electronic] United States
• PMID: 23715154 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Thymine Nucleotides
• Protein Serine-Threonine Kinases
• STK11 protein, human
• Stk11 protein, mouse
• AMP-Activated Protein Kinase Kinases
• AMP-Activated Protein Kinases
• Nucleoside-Phosphate Kinase
• dTMP kinase
• Hras protein, mouse
• Proto-Oncogene Proteins p21(ras)
• thymidine 5'-triphosphate

Topics

• AMP-Activated Protein Kinase Kinases
• AMP-Activated Protein Kinases
• Animals
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, metabolism)
• Cell Death
• Cell Line, Tumor
• DNA Damage
• DNA Replication
• Gene Knockdown Techniques
• Genomics
• High-Throughput Screening Assays
• Humans
• Lung Neoplasms (drug therapy, genetics, metabolism, pathology)
• Metabolomics
• Mice
• Models, Genetic
• Molecular Targeted Therapy
• Nucleoside-Phosphate Kinase (genetics, metabolism)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Proto-Oncogene Proteins p21(ras) (genetics, metabolism)
• RNA Interference
• Thymine Nucleotides (metabolism)