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Undermining Glutaminolysis Bolsters Chemotherapy While NRF2 Promotes Chemoresistance in KRAS-Driven Pancreatic Cancers
Open accessPublished version of a preprint
Abstract
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.
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Limiting glutamine use combined with chemotherapy halts pancreatic tumor growth in preclinical mouse models and is not toxic to normal cells.
“Limiting glutamine use combined with chemotherapy is a viable means to halt pancreatic tumor growth in preclinical mouse models and is not toxic to normal cells58,60,65.”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [60]
Oncogenic KRAS activates the NRF2 antioxidant system by inducing NRF2 expression and constitutively activating NRF2-controlled genes to maintain redox balance and promote tumorigenesis.
“In addition to activating the GOT2/GOT1/Malic Enzyme 1 (ME1) pathway, oncogenic KRAS activates the NRF2 antioxidant system by inducing NRF2 expression59,60 and by constitutively activating the battery of genes controlled by NRF2 to maintain the redox balance and promote tumorigenesis61.”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [60]
NRF2 activation causes glutamine dependence in KRAS-mutant lung and pancreatic cancer cells and preclinical mouse models.
“The activation of NRF2 causes glutamine dependence in KRAS mutant lung and pancreatic cancers cells and preclinical mouse models60,62,63, and BRAF mutants can similarly activate NRF2 to promote reactive oxygen species (ROS) detoxification59.”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [60]
Impairing glutamine metabolism induces sensitivity in gemcitabine-resistant pancreatic cancer cells.
“Impairing glutamine metabolism also induces sensitivity in gemcitabine-resistant pancreatic cancer cells16,84,85.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [85]
While NRF2 induces chemoresistance in KRAS-driven cancers, suppressing glutamine metabolism leads to weakened chemoresistance in these cancer cells.
“Consistent with these findings, while NRF2 induces chemoresistance in KRAS-driven cancers, suppressing glutamine metabolism leads to weakened chemoresistance in these cancer cells85.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [85]
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Metadata
- Authors
- Mukhopadhyay, S., Goswami, D., Adiseshaiah, P. P., Burgan, W., Yi, M., Guerin, T. M., Kozlov, S. V., Nissley, D. V., & McCormick, F.
- Affiliations
- Frederick National Laboratory for Cancer Research (US)
- University of California, San Francisco (US)
- Corresponding author
- McCormick, Frank
- ORCID
- Venue
- Cancer Research
- Published
- 2020-04-15
- Volume
- 80
- Issue
- 8
- Pages
- 1630-1643
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC7185043
- OpenAlex
- W2998854578
- Cited by
- 279
- References
- 54
- Citations by year
- 2026: 22 · 2025: 28 · 2024: 52 · 2023: 48 · 2022: 34 · 2021: 67 · 2020: 27
- FWCI
- 15.98
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- HHS | NIH | National Cancer Institute (HHSN261200800001E)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- pancreatic cancer, KRAS mutation, chemoresistance, Nrf2, glutaminolysis, glutamine metabolism, glutaminase inhibitors, gemcitabine, metabolic reprogramming, stress granules, chemosensitization
- MeSH terms
- Gemcitabine, Animals, Antimetabolites, Antineoplastic, Deoxycytidine, Glutaminase, Glutamine, Humans, Mice, Nude, Mutation, Neoplasm Proteins, Pancreatic Neoplasms, Prognosis, Random Allocation, Up-Regulation, Proto-Oncogene Proteins p21(ras), Drug Resistance, Neoplasm, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Tissue Array Analysis, NF-E2-Related Factor 2, Mice, Heterografts
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