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Cancer Res. 2020 Jan 7. pii: canres.1363.2019. doi: 10.1158/0008-5472.CAN-19-1363. [Epub ahead of print]

Undermining glutaminolysis bolsters chemotherapy while NRF2 promotes chemoresistance in KRAS-driven pancreatic cancers.

Author information

1
National Cancer Institute- RAS Initiative, Frederick National Laboratory for Cancer Research.
2
NCI RAS Initiative/Cancer Research Technology Program, Frederick National Laboratory for Cancer Research.
3
Nanotechnology Characterization Laboratory, Advanced Technology Program, SAIC-Frederick, Inc.,, Frederick National Laboratory for Cancer Research.
4
NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research.
5
Center for Advanced Preclinical Research, SAIC at Frederick National Laboratory for Cancer Research.
6
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco Frank.Mccormick@ucsf.edu.

Abstract

Pancreatic cancer is a disease with limited therapeutic options. Resistance to chemotherapies poses a significant clinical challenge for pancreatic cancer patients and contributes to a high rate of recurrence. Here we showed that oncogenic KRAS, a critical driver of pancreatic cancer, promotes metabolic reprogramming and upregulates NRF2, a master regulator of the antioxidant network. NRF2 contributed to chemoresistance and was associated with a poor prognosis in pancreatic cancer patients. NRF2 activation metabolically rewired and elevated pathways involved in glutamine metabolism. This curbed chemoresistance in KRAS-mutant pancreatic cancers. Additionally, 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 pancreatic cancer patients harboring KRAS mutation.

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