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

Yan Liu1, Kevin Marks, Glenn S Cowley

  • 1Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

Cancer Discovery
|May 30, 2013
PubMed

Insights

LKB1-mutant lung cancers exhibit nucleotide metabolism deficits. Inhibiting deoxythymidylate kinase (DTYMK) shows therapeutic promise for these aggressive tumors.

Area of Science:

  • Molecular oncology
  • Cancer metabolism
  • Tumor suppressor pathways

Background:

  • The LKB1/STK11 tumor suppressor is crucial for cell growth, polarity, motility, and metabolism.
  • LKB1 is inactivated in 25-30% of non-small cell lung carcinomas, often alongside KRAS mutations.

Purpose of the Study:

  • To identify novel therapeutic targets in KRAS-driven, LKB1-mutant lung cancers.
  • To investigate the metabolic vulnerabilities associated with LKB1 deficiency in lung cancer.

Main Methods:

  • High-throughput RNA interference screens in genetically engineered mouse models of lung cancer.
  • Comparative global metabolite profiling of LKB1-deficient versus LKB1-wild-type lung cancer cell lines.
  • Validation in both mouse and human lung cancer cell lines.

Main Results:

  • Deoxythymidylate kinase (DTYMK) was identified as synthetically lethal with LKB1 deficiency.
  • LKB1-null lung cancer cells displayed significantly reduced nucleotide metabolites.
  • LKB1-mutant lung cancers are hypersensitive to DTYMK inhibition due to nucleotide metabolism deficits.

Conclusions:

  • LKB1-mutant lung cancers possess specific vulnerabilities in nucleotide metabolism.
  • DTYMK represents a promising therapeutic target for treating KRAS-driven, LKB1-mutant non-small cell lung carcinoma.

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