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

Overview

MeSH Major

  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms
  • Nucleoside-Phosphate Kinase
  • Protein-Serine-Threonine Kinases

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

publication date

  • August 2013

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3753578

Digital Object Identifier (DOI)

  • 10.1158/2159-8290.CD-13-0015

PubMed ID

  • 23715154

Additional Document Info

start page

  • 870

end page

  • 9

volume

  • 3

number

  • 8