title: 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.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Kevin
authors.initials: K
authors.lastname: Marks
authors.forename: Glenn S
authors.initials: GS
authors.lastname: Cowley
authors.forename: Julian
authors.initials: J
authors.lastname: Carretero
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Liu
authors.forename: Thomas J F
authors.initials: TJ
authors.lastname: Nieland
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Xu
authors.forename: Travis J
authors.initials: TJ
authors.lastname: Cohoon
authors.forename: Peng
authors.initials: P
authors.lastname: Gao
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Zhao
authors.initials: Z
authors.lastname: Chen
authors.forename: Abigail B
authors.initials: AB
authors.lastname: Altabef
authors.forename: Jeremy H
authors.initials: JH
authors.lastname: Tchaicha
authors.forename: Xiaoxu
authors.initials: X
authors.lastname: Wang
authors.forename: Sung
authors.initials: S
authors.lastname: Choe
authors.forename: Edward M
authors.initials: EM
authors.lastname: Driggers
authors.forename: Jianming
authors.initials: J
authors.lastname: Zhang
authors.forename: Sean T
authors.initials: ST
authors.lastname: Bailey
authors.forename: Norman E
authors.initials: NE
authors.lastname: Sharpless
authors.forename: D Neil
authors.initials: DN
authors.lastname: Hayes
authors.forename: Nirali M
authors.initials: NM
authors.lastname: Patel
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Janne
authors.forename: Nabeel
authors.initials: N
authors.lastname: Bardeesy
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
authors.forename: Brendan D
authors.initials: BD
authors.lastname: Manning
authors.forename: Reuben J
authors.initials: RJ
authors.lastname: Shaw
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.forename: Ralph
authors.initials: R
authors.lastname: Scully
authors.forename: Alec
authors.initials: A
authors.lastname: Kimmelman
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Byers
authors.forename: Don L
authors.initials: DL
authors.lastname: Gibbons
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
authors.forename: John V
authors.initials: JV
authors.lastname: Heymach
authors.forename: David J
authors.initials: DJ
authors.lastname: Kwiatkowski
authors.forename: William Y
authors.initials: WY
authors.lastname: Kim
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.forename: David E
authors.initials: DE
authors.lastname: Root
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death; D045744:Cell Line, Tumor; D004249:DNA Damage; D004261:DNA Replication; D055785:Gene Knockdown Techniques; D023281:Genomics; D057166:High-Throughput Screening Assays; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055432:Metabolomics; D051379:Mice; D008957:Models, Genetic; D058990:Molecular Targeted Therapy; D009703:Nucleoside-Phosphate Kinase / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D013942:Thymine Nucleotides / Q000378:metabolism
chemical_list: D013942:Thymine Nucleotides; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; C491654:Stk11 protein, mouse; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); C024157:thymidine 5'-triphosphate