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

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.

Targeting Glutaminolysis: New Perspectives to Understand Cancer Development and Novel Strategies for Potential Target Therapies

“…Lee et al reported a successful inhibition of undifferentiated pleomorphic sarcoma (UPS) tumor growth with CB-839 (135). Combination therapy of CB-839 and PARP inhibitor olaparib also showed prolonged survival in a xenograft model of ovarian cancer (136). However, Biancur et al found no antitumor effect of CB-839 in both autochthonous and subcutaneous mouse models of PDAC (130).…”

Targeting the Proline–Glutamine–Asparagine–Arginine Metabolic Axis in Amino Acid Starvation Cancer Therapy

“…Therefore, Gln deprivation may cause increased ROS due to GSH suppression [ 66 , 74 ]. Indeed, reducing cellular Gln levels during Gln withdrawal [ 75 ], GLS knockdown, or exposure of cells to the GLS inhibitor CB-839 all resulted in a robust induction of ROS in high GLS-expressing but not in low GLS-expressing ovarian cancer cells [ 76 ], further supporting the roles of GLS in ROS production…”

c-MYC and Epithelial Ovarian Cancer

“…Dual inhibition of PARP (Olaparib) and CDK4/6 (Palbociclib) inhibits the growth of ovarian cancer cells in vitro and slows down tumor growth in vivo in part by inducing homologous recombination (HR) deficiency in a MYC-dependent manner (92). Concomitant upregulation of glutaminase (GLS) and c-MYC has been observed in platinum-resistant ovarian cancer cells (93). Inhibition of GLS-a downstream target of c-MYCby CB-839 sensitizes ovarian cancer cells to PARP inhibition and prolong survival in tumor-bearing mice (93).…”