Undermining Glutaminolysis Bolsters Chemotherapy While NRF2 Promotes Chemoresistance in KRAS-Driven Pancreatic Cancers

• Published in: Cancer research (Chicago, Ill.) Vol. 80; no. 8; pp. 1630 - 1643
• Main Authors: Mukhopadhyay, Suman, Goswami, Debanjan, Adiseshaiah, Pavan P, Burgan, William, Yi, Ming, Guerin, Theresa M, Kozlov, Serguei V, Nissley, Dwight V, McCormick, Frank
• Format: Journal Article
• Language: English
• Published: United States 15-04-2020
• Subjects: Animals; Antimetabolites, Antineoplastic - pharmacology; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - mortality; Cell Line, Tumor; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Drug Resistance, Neoplasm - physiology; Gemcitabine; Glutaminase - antagonists & inhibitors; Glutamine - metabolism; Heterografts; Humans; Mice; Mice, Nude; Mutation; Neoplasm Proteins - metabolism; NF-E2-Related Factor 2 - metabolism; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - mortality; Prognosis; Proto-Oncogene Proteins p21(ras) - genetics; Random Allocation; Tissue Array Analysis; Up-Regulation
• ISSN: 0008-5472; 1538-7445; 1538-7445
• DOI: 10.1158/0008-5472.can-19-1363

Pancreatic cancer is a disease with limited therapeutic options. Resistance to chemotherapies poses a significant clinical challenge for patients with pancreatic cancer and contributes to a high rate of recurrence. Oncogenic KRAS, a critical driver of pancreatic cancer, promotes metabolic reprogramming and upregulates NRF2, a master regulator of the antioxidant network. Here, we show that NRF2 contributed to chemoresistance and was associated with a poor prognosis in patients with pancreatic cancer. NRF2 activation metabolically rewired and elevated pathways involved in glutamine metabolism. This curbed chemoresistance in KRAS-mutant pancreatic cancers. In addition, manipulating glutamine metabolism restrained the assembly of stress granules, an indicator of chemoresistance. Glutaminase inhibitors sensitized chemoresistant pancreatic cancer cells to gemcitabine, thereby improving the effectiveness of chemotherapy. This therapeutic approach holds promise as a novel therapy for patients with pancreatic cancer harboring KRAS mutation. SIGNIFICANCE: These findings illuminate the mechanistic features of KRAS-mediated chemoresistance and provide a rationale for exploiting metabolic reprogramming in pancreatic cancer cells to confer therapeutic opportunities that could be translated into clinical trials. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/8/1630/F1.large.jpg.