Combined thioredoxin reductase and glutaminase inhibition exerts synergistic anti-tumor activity in MYC-high high-grade serous ovarian carcinoma

Approximately 50%-55% of high-grade serous ovarian carcinoma (HGSOC) patients have MYC oncogenic pathway activation. Because MYC is not directly targetable, we have analyzed molecular pathways enriched in MYC-high HGSOC tumors to identify potential therapeutic targets. Here, we report that MYC-high HGSOC tumors show enrichment in genes controlled by NRF2, an antioxidant signaling pathway, along with increased thioredoxin redox activity. Treatment of MYChigh HGSOC tumors cells with US Food and Drug Administration (FDA)-approved thioredoxin reductase 1 (TrxR1) inhibitor auranofin resulted in significant growth suppression and apoptosis in MYC-high HGSOC cells in vitro and also significantly reduced tumor growth in an MYC-high HGSOC patient-derived tumor xenograft. We found that auranofin treatment inhibited glycolysis in MYC-high cells via oxidation-induced GAPDH inhibition. Interestingly, in response to auranofin-induced glycolysis inhibition, MYC-high HGSOC cells switched to glutamine metabolism for survival. Depletion of glutamine with either glutamine starvation or glutaminase with auranofin in HGSOC cells and OVCAR-8 cell line xenograft. These findings suggest that applying a combined therapy of GLS1 inhibitor and TrxR1 inhibitor could effectively treat MYC-high HGSOC patients.

Automated summary

Approximately 50%-55% of HGSOC patients have MYC oncogenic pathway activation. Enrichment of NRF2-controlled genes and increased thioredoxin redox activity were observed in MYC-high HGSOC tumors. Treatment with the TrxR1 inhibitor auranofin resulted in growth inhibition and apoptosis in MYC-high HGSOC cells, and auranofin also significantly reduced tumor growth in a patient-derived tumor xenograft model. Inhibition of glycolysis in MYC-high cells led to a switch to glutamine metabolism for survival. Depletion of glutamine, either through starvation or with auranofin, effectively reduced tumor growth in HGSOC cells and xenograft models, suggesting a potential combination therapy for MYC-high HGSOC patients.