Inhibition of the MYC-Regulated Glutaminase Metabolic Axis Is an Effective Synthetic Lethal Approach for Treating Chemoresistant Ovarian Cancers

Cancer Res. 2020 Oct 15;80(20):4514-4526. doi: 10.1158/0008-5472.CAN-19-3971. Epub 2020 Aug 28.

Abstract

Amplification and overexpression of the MYC oncogene in tumor cells, including ovarian cancer cells, correlates with poor responses to chemotherapy. As MYC is not directly targetable, we have analyzed molecular pathways downstream of MYC to identify potential therapeutic targets. Here we report that ovarian cancer cells overexpressing glutaminase (GLS), a target of MYC and a key enzyme in glutaminolysis, are intrinsically resistant to platinum-based chemotherapy and are enriched with intracellular antioxidant glutathione. Deprivation of glutamine by glutamine-withdrawal, GLS knockdown, or exposure to the GLS inhibitor CB-839 resulted in robust induction of reactive oxygen species in high GLS-expressing but not in low GLS-expressing ovarian cancer cells. Treatment with CB-839 rendered GLShigh cells vulnerable to the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib, and prolonged survival in tumor-bearing mice. These findings suggest consideration of applying a combined therapy of GLS inhibitor and PARP inhibitor to treat chemoresistant ovarian cancers, especially those with high GLS expression. SIGNIFICANCE: Targeting glutaminase disturbs redox homeostasis and nucleotide synthesis and causes replication stress in cancer cells, representing an exploitable vulnerability for the development of effective therapeutics. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/20/4514/F1.large.jpg.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Benzeneacetamides / administration & dosage
  • Benzeneacetamides / pharmacology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Drug Resistance, Neoplasm / drug effects*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Glutaminase / antagonists & inhibitors
  • Glutaminase / metabolism*
  • Glutamine / genetics
  • Glutamine / metabolism
  • Glutathione / metabolism
  • Humans
  • Mice, Nude
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism
  • Phthalazines / administration & dosage
  • Phthalazines / pharmacology
  • Piperazines / administration & dosage
  • Piperazines / pharmacology
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Thiadiazoles / administration & dosage
  • Thiadiazoles / pharmacology
  • Xenograft Model Antitumor Assays

Substances

  • Benzeneacetamides
  • CB-839
  • Phthalazines
  • Piperazines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Proto-Oncogene Proteins c-myc
  • Thiadiazoles
  • Glutamine
  • Glutaminase
  • Glutathione
  • olaparib