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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Shen, Y-A; Hong, J; Asaka, R; Asaka, S; Hsu, F-C; Suryo Rahmanto, Y; Jung, J-G; Chen, Y-W; Yen, T-T; Tomaszewski, A; Zhang, C; Attarwala, N; DeMarzo, AM; Davidson, B; Chuang, C-M; Chen, X; Gaillard, S; Le, A; Shih, I-M; Wang, T-L

Published Date

  • October 15, 2020

Published In

Volume / Issue

  • 80 / 20

Start / End Page

  • 4514 - 4526

PubMed ID

  • 32859605

Pubmed Central ID

  • 32859605

Electronic International Standard Serial Number (EISSN)

  • 1538-7445

Digital Object Identifier (DOI)

  • 10.1158/0008-5472.CAN-19-3971

Language

  • eng

Conference Location

  • United States