Dependence on the Pyrimidine Biosynthetic Enzyme DHODH Is a Synthetic Lethal Vulnerability in Mutant KRAS-Driven Cancers

Cell Chem Biol. 2018 Jun 21;25(6):705-717.e11. doi: 10.1016/j.chembiol.2018.03.005. Epub 2018 Apr 5.

Abstract

Activating KRAS mutations are major oncogenic drivers in multiple tumor types. Synthetic lethal screens have previously been used to identify targets critical for the survival of KRAS mutant cells, but their application to drug discovery has proven challenging, possibly due in part to a failure of monolayer cultures to model tumor biology. Here, we report the results of a high-throughput synthetic lethal screen for small molecules that selectively inhibit the growth of KRAS mutant cell lines in soft agar. Chemoproteomic profiling identifies the target of the most KRAS-selective chemical series as dihydroorotate dehydrogenase (DHODH). DHODH inhibition is shown to perturb multiple metabolic pathways. In vivo preclinical studies demonstrate strong antitumor activity upon DHODH inhibition in a pancreatic tumor xenograft model.

Keywords: KRAS mutation; cancer metabolism; chemoproteomics; pyrimidine biosynthesis; synthetic lethality.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Proliferation / drug effects
  • Dihydroorotate Dehydrogenase
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Female
  • Humans
  • Mice
  • Mice, SCID
  • Mutation
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / metabolism
  • Neoplasms, Experimental / pathology
  • Oxidoreductases Acting on CH-CH Group Donors / antagonists & inhibitors
  • Oxidoreductases Acting on CH-CH Group Donors / metabolism*
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Proto-Oncogene Proteins p21(ras) / antagonists & inhibitors
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism*
  • Pyrimidines / chemistry
  • Pyrimidines / metabolism*
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Dihydroorotate Dehydrogenase
  • Enzyme Inhibitors
  • KRAS protein, human
  • Pyrimidines
  • Small Molecule Libraries
  • Oxidoreductases Acting on CH-CH Group Donors
  • Proto-Oncogene Proteins p21(ras)
  • pyrimidine