Compensatory metabolic networks in pancreatic cancers upon perturbation of glutamine metabolism
Open accessAbstract
Pancreatic ductal adenocarcinoma is a notoriously difficult-to-treat cancer and patients are in need of novel therapies. We have shown previously that these tumours have altered metabolic requirements, making them highly reliant on a number of adaptations including a non-canonical glutamine (Gln) metabolic pathway and that inhibition of downstream components of Gln metabolism leads to a decrease in tumour growth. Here we test whether recently developed inhibitors of glutaminase (GLS), which mediates an early step in Gln metabolism, represent a viable therapeutic strategy. We show that despite marked early effects on in vitro proliferation caused by GLS inhibition, pancreatic cancer cells have adaptive metabolic networks that sustain proliferation in vitro and in vivo . We use an integrated metabolomic and proteomic platform to understand this adaptive response and thereby design rational combinatorial approaches. We demonstrate that pancreatic cancer metabolism is adaptive and that targeting Gln metabolism in combination with these adaptive responses may yield clinical benefits for patients.
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Not all KRAS tumors are sensitive to inhibition of glutamine metabolism in vivo.
“Consistently, not all KRAS tumors are sensitive to inhibition of glutamine metabolism in vivo74,75, indicating that a deeper understanding is required of the context in which KRAS-driven cancers would be most sensitive to agents that target this metabolic pathway.”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [75]
Oncogenic Ras drives glutamine anaplerosis to supply carbon for the TCA cycle, glutathione biosynthesis for ROS detoxification, and a non-canonical malate-aspartate shuttle for NADPH production.
“Oncogenic Ras also drives glutamine anaplerosis to provide a significant source of carbon for TCA cycle, biosynthesis of glutathione necessary to detoxify reactive oxygen species (ROS), and enables a non-canonical malate-aspartate shuttle to generate NADPH for redox balance198”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [198]
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“Tumor cells are highly adaptable and alter nutrient uptake and metabolic networks to resist single-agent glutaminase inhibition (17, 18).”
BackgroundSayin, V. I., LeBoeuf, S. E., Singh, S. X., Davidson, S. M., Biancur, D., Guzelhan, B. S., Alvarez, S. W., Wu, W. L., Karakousi, T. R., Zavitsanou, A. M., et al. (2017) · eLife · doi:10.7554/elife.28083 · Cited by 231 · see citing works
“, 2014), inhibiting this pathway has led to limited responses in both pre-clinical models (Davidson et al., 2016; Biancur et al., 2017) and ongoing clinical trials; highlighting the importance of identifying genetic subtypes of cancer that may have a greater dependency on glutamine.”
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Cancer Cells Don’t Live Alone: Metabolic Communication within Tumor Microenvironments
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“Tissue of origin and local microenvironment influence metabolic fitness and rewiring in cancer (Biancur et al., 2017; Davidson et al., 2016; Lee et al., 2020b; Mayers et al., 2016), while certain genetic or epigenetic modifiers and tumor plasticity confer differential sensitivity to metabolic interventions (Li et al.”
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The Diverse Functions of Non-Essential Amino Acids in Cancer
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“While these glutaminase inhibitors are effective against most cancer cells grown in culture, often times they are less effective in mouse models of cancer [38,39].”
BackgroundFrom correlation to causation: analysis of metabolomics data using systems biology approaches
Rosato, A., Tenori, L., Cascante, M., de Atauri, P., dos Santos, V. A. P. M., & Saccenti, E. (2018) · Metabolomics · doi:10.1007/s11306-018-1335-y · Cited by 209 · see citing works
“For example, the inhibition at an early of glutamine metabolism induces extensive changes in the metabolism of other amino acids but also of the oxidation of branched-chain fatty acids in pancreatic ductal adenocarcinoma cells (Biancur et al. 2017).”
BackgroundCytosolic Aspartate Availability Determines Cell Survival When Glutamine Is Limiting
Alkan, H. F., Walter, K. E., Luengo, A., Madreiter‐Sokolowski, C. T., Stryeck, S., Lau, A. N., Zoughbi, W. A., Lewis, C. A., Thomas, C. J., Höefler, G., et al. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.07.021 · Cited by 205 · see citing works
Dietary Approaches to Cancer Therapy
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“Importantly, unlike GLS, whose ablation does not have an overt effect on PDAC development in vivo (Biancur et al., 2017), GLUL germline ablation leads to a significant delay in disease progression (Figures 4A–4C), which is accompanied by decreased O-glycosylation and cell proliferation (Figures 4D and 4E).”
BackgroundDysregulation of glutaminase and glutamine synthetase in cancer
Matés, J. M., Campos-Sandoval, J. A., Santos-Jiménez, J. D. L., & Márquez, J. (2019) · Cancer Letters · doi:10.1016/j.canlet.2019.09.011 · Cited by 197 · see citing works
Glutamine depletion regulates Slug to promote EMT and metastasis in pancreatic cancer
Recouvreux, M. V., Moldenhauer, M. R., Galenkamp, K. M. O., Jung, M., James, B., Zhang, Y., Lowy, A., Bagchi, A., & Commisso, C. (2020) · Journal of Experimental Medicine · doi:10.1084/jem.20200388 · Cited by 181 · see citing works
Selective alanine transporter utilization creates a targetable metabolic niche in pancreatic cancer
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“Page 27 compensation and failed to illicit an impact on PDAC tumor growth in vivo (40).”
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“However, Biancur et al. found no antitumor effect of CB-839 in both autochthonous and subcutaneous mouse models of PDAC (130).”
BackgroundInfluentialHarnessing metabolic dependencies in pancreatic cancers
Encarnación-Rosado, J., & Kimmelman, A. C. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-021-00431-7 · Cited by 180 · see citing works
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“Tissues were processed as previously described (53).”
Self-citationEGFR-Pak signaling selectively regulates glutamine deprivation-induced macropinocytosis
Lee, S.-W., Zhang, Y., Jung, M., Cruz, N., Alas, B., & Commisso, C. (2019) · Developmental Cell · doi:10.1016/j.devcel.2019.05.043 · Cited by 172 · see citing works
“PDAC cancer cells are exquisitely sensitive to glutamine depletion, as they utilize glutamine as a major carbon and nitrogen source for their growth and glutamine is the most depleted amino acid in human PDAC tumors (Biancur et al., 2017; Cluntun et al., 2017; Hensley et al., 2013; Hosios et al., 2016; Hui et al., 201…”
BackgroundDeubiquitinases Maintain Protein Homeostasis and Survival of Cancer Cells upon Glutathione Depletion
Harris, I. S., Endress, J. E., Coloff, J. L., Selfors, L. M., McBrayer, S. K., Rosenbluth, J. M., Takahashi, N., Dhakal, S., Koduri, V., Oser, M. G., et al. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.01.020 · Cited by 168 · see citing works
“Inhibition of GLS activity was previously shown to synergize with BSO in breast cancer cells, potentially by reducing glutamate levels and impairing GSH synthesis to a greater degree than BSO alone (Beatty et al., 2017; Biancur et al., 2017).”
BackgroundAdapt and conquer: Metabolic flexibility in cancer growth, invasion and evasion
Kreuzaler, P. A., Panina, Y., Segal, J., & Yuneva, M. (2019) · Molecular Metabolism · doi:10.1016/j.molmet.2019.08.021 · Cited by 151 · see citing works
“Other systems have been reported to have a remarkable ability to adapt to therapies targeted at glutaminolysis; it would thus be interesting to compare the flexibility of those same systems under more restrained circumstances such as hypoxia [100].”
BackgroundNitrogen Metabolism in Cancer and Immunity
Kurmi, K., & Haigis, M. C. (2020) · Trends in Cell Biology · doi:10.1016/j.tcb.2020.02.005 · Cited by 160 · see citing works
“Nevertheless, use of CB-839 as a GLS inhibitor is being investigated as a cancer therapeutic in the clinic for its potential efficacy [23, 62, 63].”
BackgroundLipid Metabolism and Lipid Droplets in Pancreatic Cancer and Stellate Cells
Sunami, Y., Rebelo, A., & Kleeff, J. H. (2017) · Cancers · doi:10.3390/cancers10010003 · Cited by 154 · see citing works
“In addition, the mice treated with CB-839 show marginally shorter survival than the group without CB-839 treatment [110].”
BackgroundThe plasticity of pancreatic cancer metabolism in tumor progression and therapeutic resistance
Biancur, D. E., & Kimmelman, A. C. (2018) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2018.04.011 · Cited by 151 · see citing works
“Given that GLS is so proximal in the pathways utilizing glutamine carbon, it is likely that these tumors can rapidly rewire their metabolism to generate alternative sources of glutamate as a mechanism of resistance [69].”
BackgroundInfluentialSelf-citationBarriers and opportunities for gemcitabine in pancreatic cancer therapy
Beutel, A. K., & Halbrook, C. J. (2023) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00331.2022 · Cited by 150 · see citing works
CD9 identifies pancreatic cancer stem cells and modulates glutamine metabolism to fuel tumour growth
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Targeting pancreatic cancer metabolic dependencies through glutamine antagonism
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“To target this metabolic dependency, we previously tested GLS inhibition in pancreatic cancer models 12 .”
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Pancreatic Cancer: Molecular Characterization, Clonal Evolution and Cancer Stem Cells
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“Nagarajan and coworkers have developed an integrative genomic approach to identify deregulated components of the glycolytic apparatus in PDAC; using this approach, they have identified a pathway involving paraoxonase 2 (PON2) as a regulator of the glucose transporter 1 (GLUT1) and consequential activation of the AMP-a…”
BackgroundResultInfluentialHNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer
Brunton, H., Caligiuri, G., Cunningham, R., Upstill‐Goddard, R., Bailey, U., Garner, I., Nourse, C., Dreyer, S. B., Jones, M. D., Moran‐Jones, K., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107625 · Cited by 124 · see citing works
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Metabolic Regulation of Redox Balance in Cancer
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“However, in vivo, GLS1 inhibition by CB-839 in genetically engineered mouse models of pancreatic cancer failed to show any therapeutic effect [103].”
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Uncovering the Role of N-Acetyl-Aspartyl-Glutamate as a Glutamate Reservoir in Cancer
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“Although a recent study has provided a broad metabolic profile of potential upregulated pathways upon glutaminase inhibition, the exact compensatory mechanism and causes of the resistance are still unknown (Biancur et al., 2017).”
BackgroundBranched-chain amino acids sustain pancreatic cancer growth by regulating lipid metabolism
Lee, J. H., Cho, Y.-R., Kim, J. H., Kim, J.-W., Nam, H. Y., Kim, S. W., & Son, J. (2019) · Experimental & Molecular Medicine · doi:10.1038/s12276-019-0350-z · Cited by 111 · see citing works
The Pleiotropic Effects of Glutamine Metabolism in Cancer
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“Withdrawing PDAC cells of one of their favored carbon source, glutamine, leads to attempts by the cell to acquire carbon from alternative pathways, such as oxidation of branched chain fatty acids [99].”
BackgroundTargeting the tumor microenvironment: Potential strategy for cancer therapeutics
Babar, Q., Saeed, A., Tabish, T. A., Sarwar, M., & Thorat, N. D. (2023) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2023.166746 · Cited by 109 · see citing works
Liver-Type Glutaminase GLS2 Is a Druggable Metabolic Node in Luminal-Subtype Breast Cancer
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Targeting glutamine metabolism slows soft tissue sarcoma growth
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“CB-839 has also been previously examined in KP models of lung cancer and PDAC 33,34 .”
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Glutaminase isoenzymes in the metabolic therapy of cancer
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Glutamine Metabolism in Brain Tumors
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Defining a metabolic landscape of tumours: genome meets metabolism
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Glutamine addiction in tumor cell: oncogene regulation and clinical treatment
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“However, there is a lack of research on the potential compensatory effects of tumor cells when the metabolism of glutamine is blocked, which can impact the effectiveness of therapy [178].”
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Metabolism in the Tumor Microenvironment
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Glutamine Synthetase as a Therapeutic Target for Cancer Treatment
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Organoids: An intermediate modeling platform in precision oncology
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Targeting extracellular nutrient dependencies of cancer cells
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“Glutaminase inhibition with a phase 2 clinical drug, CB-839, strongly impairs the in vitro proliferation of PDAC cells but does not impact tumor growth in an autochthonous PDAC model [132].”
BackgroundAmino acid metabolism reprogramming: shedding new light on T cell anti-tumor immunity
Zheng, Y., Yao, Y., Ge, T., Ge, S., Jia, R., Song, X., & Zhuang, A. (2023) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-023-02845-4 · Cited by 86 · see citing works
“As mentioned earlier, pancreatic cancer cells have a compensatory metabolic network for GLS inhibitors [197].”
BackgroundFunctional Genomics Identifies Metabolic Vulnerabilities in Pancreatic Cancer
Biancur, D. E., Kapner, K. S., Yamamoto, K., Banh, R. S., Neggers, J. E., Sohn, A. S. W., Wu, W., Manguso, R. T., Brown, A., Root, D. E., et al. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.10.018 · Cited by 82 · see citing works
Self-citationDissecting cell-type-specific metabolism in pancreatic ductal adenocarcinoma
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Mitochondrial Metabolism in PDAC: From Better Knowledge to New Targeting Strategies
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“All analysis involved an MS3-based TMT (tandem mass tag) method as previously mentioned and mass spectra were processed as described earlier (26, 29).”
MethodSelf-citationRecouvreux, M. V., Grenier, S. F., Zhang, Y., Esparza, E., Lambies, G., Galapate, C. M., Maganti, S., Duong‐Polk, K., Bhullar, D., Naeem, R. F., et al. (2023) · Nature Cancer · doi:10.1038/s43018-023-00649-1 · Cited by 77 · see citing works
“In preclinical mouse models of PDAC, the pharmacological inhibition of GLS did not display antitumor activity; this was attributed to intratumoral compensatory responses 16 .”
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Self-citationExploiting pancreatic cancer metabolism: challenges and opportunities
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“…studies with CB-839 showed that, despite marked initial growth inhibition, pancreatic cancer cells develop rapid adaptive metabolic rewiring to overcome initial glutamine dependency, and that combinatorial metabolic inhibition may be required to yield clinical bene fi ts for patients [60].”
Ketogenic HMG‐CoA lyase and its product β‐hydroxybutyrate promote pancreatic cancer progression
Gouirand, V., Gicquel, T., Lien, E. C., Jaune, E., Costa, Q. D., Finetti, P., Metay, E., Duluc, C., Mayers, J. R., Audebert, S., et al. (2022) · The EMBO Journal · doi:10.15252/embj.2021110466 · Cited by 75 · see citing works
“For example, pancreatic cancer cells are sensitive to inhibitors of glutamine metabolism in vitro , but adapt to glutaminase inhibitors when grown as PDA tumors in mouse models (Biancur et al , 2017).”
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Tumor microenvironmental nutrients, cellular responses, and cancer
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Integrating bioinformatics approaches for a comprehensive interpretation of metabolomics datasets
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“Biochemical and ontology databases lack entries for the 385 metabolites identified in non-obese diabetic mice [30].”
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“Likewise, Gln sensitivity is also regulated by a bidirectional amino acid transporter SLC7A5/SLC3A2, which regulates the simultaneous efflux of L-Glu out of cells and the transport of other amino acids into cells [118].”
BackgroundA second Warburg‐like effect in cancer metabolism: The metabolic shift of glutamine‐derived nitrogen
Kodama, M., & Nakayama, K. I. (2020) · BioEssays · doi:10.1002/bies.202000169 · Cited by 65 · see citing works
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“Similar metabolic compensation has been observed in KPC mice treated with the glutaminase inhibitor CB-839 [112], further emphasising the metabolic plasticity of PDAC tumours [113, 114].”
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NCOA4 maintains murine erythropoiesis via cell autonomous and non-autonomous mechanisms
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“were performed as previously described.(19,20) Briefly, 50 μg of”
MethodSelf-citationThe Role of Mitochondria in the Chemoresistance of Pancreatic Cancer Cells
Fu, Y., Ricciardiello, F., Yang, G., Qiu, J., Huang, H., Xiao, J., Cao, Z., Zhao, F., Liu, Y., Luo, W., et al. (2021) · Cells · doi:10.3390/cells10030497 · Cited by 57 · see citing works
“Importantly, in contrast to GLS, whose inhibition does not have a significant effect on PC development in vivo [87], GLUL ablation causes a significant delay in disease progression, which is associated with decreased O-glycosylation and cell proliferation, underling the importance of the HBP in PC.”
BackgroundMetabolic dependencies and targets in ovarian cancer
Zhang, Y., Wang, Y., Zhao, G., Oršulić, S., & Matei, D. E. (2023) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2023.108413 · Cited by 59 · see citing works
Zhou, T., Yang, Y., Chen, Q., & Xie, L. (2019) · Stem Cells International · doi:10.1155/2019/8928934 · Cited by 73 · see citing works
KRAS: the Achilles’ heel of pancreas cancer biology
Drizyte‐Miller, K., Talabi, T., Somasundaram, A., Cox, A. D., & Der, C. J. (2025) · Journal of Clinical Investigation · doi:10.1172/jci191939 · Cited by 63 · see citing works
“The glutaminase 1 inhibitor telaglenastat (CB-839) has shown limited clinical efficacy in advanced solid tumors when combined with PARP inhibitors (NCT03875313), perhaps owing to rapid metabolic adaptations that overcome glutamine dependency (111).”
Metabolic alterations in hereditary and sporadic renal cell carcinoma
Coffey, N. J., & Simon, M. C. (2024) · Nature Reviews Nephrology · doi:10.1038/s41581-023-00800-2 · Cited by 54 · see citing works
“111,173).”
Chen, M., Tong, X., Sun, Y., Dong, C., Li, C., Wang, C., Zhang, M., Wen, Y., Ye, P., Li, R., et al. (2024) · Biomaterials · doi:10.1016/j.biomaterials.2024.122574 · Cited by 53 · see citing works
Singleton, D. C., Dechaume, A.-L., Murray, P. M., Katt, W. P., Baguley, B. C., & Leung, E. Y. (2020) · BMC Cancer · doi:10.1186/s12885-020-06885-3 · Cited by 54 · see citing works
Physiological Media in Studies of Cell Metabolism
Golikov, M. V., Треворович, В.-Э. В., Smirnova, O. A., & Ivanov, A. V. (2022) · Molecular Biology · doi:10.1134/s0026893322050077 · Cited by 51 · see citing works
“An example of such a discrepancy in cellular metabolism studies is very strong antiproliferative activity of glutaminase inhibitors against various types of cancer lines in vitro and the absence of antitumor activity of these compounds in vivo, as is shown by the example of pancreatic cancer [26].”
Background
- Authors
- Biancur, D. E., Paulo, J. A., Małachowska, B., Quiles Del Rey, M., Sousa, C. M., Wang, X., Sohn, A. S. W., Chu, G. C., Gygi, S. P., Harper, J. W., Fendler, W., Mancias, J. D., & Kimmelman, A. C.
- Affiliations
- NYU Langone Health (US)
- Medical University of Warsaw (PL)
- Dana-Farber Cancer Institute (US)
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Corresponding author
- Mancias, Joseph D.
- Kimmelman, Alec C.
- ORCID
- Venue
- Nature Communications
- Published
- 2017-07-03
- Volume
- 8
- Issue
- 1
- Pages
- 15965-15965
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5500878
- OpenAlex
- W2729334679
- Cited by
- 315
- References
- 55
- Citations by year
- 2026: 25 · 2025: 41 · 2024: 36 · 2023: 30 · 2022: 39 · 2021: 29 · 2020: 51 · 2019: 41 · 2018: 15 · 2017: 8
- FWCI
- 10.55
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Calithera Biosciences (CB839)
- Fundacja na rzecz Nauki Polskiej
- National Institutes of Health (KL2TR001100)
- National Cancer Institute (R01CA188048, R01CA157490, P01CA117969)
- National Institute of General Medical Sciences (R01GM095567)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK098285, K01DK098285)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- pancreatic ductal adenocarcinoma, glutamine metabolism, glutaminase inhibition, metabolic adaptation, tumor cell proliferation, cancer metabolism, metabolomics, proteomics, combination therapy
- MeSH terms
- Animals, Female, Glutaminase, Glutamine, Humans, Male, Mice, Inbred C57BL, Pancreatic Neoplasms, Xenograft Model Antitumor Assays, Proteomics, Cell Line, Tumor, Cell Proliferation, Mice, Metabolic Networks and Pathways
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