Inhibition of the MYC-regulated glutaminase metabolic axis is an effective synthetic lethal approach for treating chemoresistant ovarian cancers

Yao An Shen, Jiaxin Hong, Ryoichi Asaka, Shiho Asaka, Fang Chi Hsu, Yohan Suryo Rahmanto, Jin Gyoung Jung, Yu Wei Chen, Ting Tai Yen, Alicja Tomaszewski, Cissy Zhang, Nabeel Attarwala, Angelo M. DeMarzo, Ben Davidson, Chi Mu Chuang, Xi Chen, Stephanie Gaillard, Anne Le, Ie Ming Shih, Tian Li Wang

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4415-4526
Number of pages112
JournalCancer Research
Volume80
Issue number20
DOIs
Publication statusPublished - Oct 15 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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