Targeting Glutaminolysis Potentiates the Efficacy of Chemotherapy in RAS-driven Pancreatic Cancers

Abstract Pancreatic cancer is an extremely aggressive and deadly malignancy. Despite a detailed understanding of pancreatic ductal adenocarcinoma (PDAC)'s biology, the outcome of the current therapeutic regimen remains grim. Chemotherapeutic treatment is one of the first-line systemic treatments for PDAC. However, creating resistance against chemotherapy remains a major challenge. Oncogenic K-Ras mutation is one of the most common events responsible for the initiation and progression of PDAC. K-Ras mutation also promotes the activation of a transcription factor called NRF2 that is crucial for tumor development and pancreatic cancer proliferation. Our study detects differential basal levels of NRF2 in a panel of PDAC cell lines. We hypothesized that this phenomenon might reflect a greater intrinsic capacity of PDAC cells to become resistant to chemotherapy. We then demonstrated that up-regulation of NRF2 creates resistance against chemotherapy in PDAC cells. Consequently, NRF2 activation rewires metabolic pathway networks. Importantly, our metabolomics analysis revealed that, upon NRF2 activation, several metabolic pathways are reprogrammed. Recent advances in tumor metabolism signify the critical role of glutamine as a key regulator of cancer therapy. Moreover, we observed that inhibiting glutamine metabolism enhances the efficacy of chemotherapeutic drugs in PDAC cells. Taken together, our finding holds promise as a novel combination therapy for patients with pancreatic cancer marked by developed resistance against chemotherapy. Finally, this treatment strategy further establishes the potential for exploiting metabolic changes in RAS-driven cancer cells that confer novel therapeutic opportunities. Citation Format: Suman Mukhopadhyay, Debanjan Goswami, Dwight V. Nissley, Frank McCormick. Targeting glutaminolysis potentiates the efficacy of chemotherapy in RAS-driven pancreatic cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 238.