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

Amplification and expression 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 MYC target and a key enzyme in glutaminolysis, are intrinsically resistant to platinum chemotherapy and are enriched in the 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 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 that applying a combined therapy of GLS inhibitor and PARP inhibitor could effectively treat chemoresistant ovarian cancers, especially those with high expression of GLS.