Pharmacological blockade of ASCT2-dependent glutamine transport leads to antitumor efficacy in preclinical models
Open accessAbstract
The unique metabolic demands of cancer cells underscore potentially fruitful opportunities for drug discovery in the era of precision medicine. However, therapeutic targeting of cancer metabolism has led to surprisingly few new drugs to date. The neutral amino acid glutamine serves as a key intermediate in numerous metabolic processes leveraged by cancer cells, including biosynthesis, cell signaling, and oxidative protection. Herein we report the preclinical development of V-9302, a competitive small molecule antagonist of transmembrane glutamine flux that selectively and potently targets the amino acid transporter ASCT2. Pharmacological blockade of ASCT2 with V-9302 resulted in attenuated cancer cell growth and proliferation, increased cell death, and increased oxidative stress, which collectively contributed to antitumor responses in vitro and in vivo. This is the first study, to our knowledge, to demonstrate the utility of a pharmacological inhibitor of glutamine transport in oncology, representing a new class of targeted therapy and laying a framework for paradigm-shifting therapies targeting cancer cell metabolism.
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Combination therapy with V-9302 and EGFR-targeted antibodies may result in even further improved efficacy.
“Building upon these promising results and in view of the 100-fold improvement in potency of V-9302 over GPNA [51], combination therapy with V-9302 and EGFR-targeted antibodies may result in even further improved efficacy.”
From Combined blockade of EGFR and glutamine metabolism in preclinical models of colorectal cancer (2020) · cites this paper as [51]
V-9302 may represent a superior treatment strategy for CRC.
“Thus, V-9302 may represent a superior treatment strategy for CRC.”
From Combined blockade of EGFR and glutamine metabolism in preclinical models of colorectal cancer (2020) · cites this paper as [51]
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- Authors
- Schulte, M. L., Fu, A., Zhao, P., Li, J., Geng, L., Smith, S. T., Kondo, J., Coffey, R. J., Johnson, M. O., Rathmell, J. C., Sharick, J. T., Skala, M. C., Smith, J. A., Berlin, J., Washington, M. K., Nickels, M. L., & Manning, H. C.
- Affiliations
- Vanderbilt University Medical Center (US)
- Veterans Health Administration (US)
- Vanderbilt University (US)
- Vanderbilt-Ingram Cancer Center (US)
- Corresponding author
- Manning, H Charles
- ORCID
- Venue
- Nature Medicine
- Published
- 2018-01-15
- Volume
- 24
- Issue
- 2
- Pages
- 194-202
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC5803339
- OpenAlex
- W2783764907
- Cited by
- 494
- References
- 42
- Citations by year
- 2026: 42 · 2025: 81 · 2024: 82 · 2023: 49 · 2022: 62 · 2021: 62 · 2020: 55 · 2019: 37 · 2018: 22
- FWCI
- 19.18
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1s10od019963-01a1, 1s10od016245-01)
- National Heart, Lung, and Blood Institute (R01HL136664)
- National Cancer Institute (R01CA211082, R01CA185747, R01CA205101, P50CA095103, R01CA046413, P30CA068485, R01CA217987, R35CA197570, P50CA236733)
- National Institute of General Medical Sciences (T32GM007105)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK058404, R01DK105550)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Cancer Research and Treatments
- Keywords
- ASCT2, glutamine transport, cancer metabolism, oxidative stress, anticancer activity, targeted cancer therapy
- MeSH terms
- Animals, Computer Simulation, Disease Models, Animal, Glutamine, Humans, Neoplasms, Signal Transduction, Minor Histocompatibility Antigens, Oxidative Stress, Amino Acid Transport System ASC, HCT116 Cells, Cell Line, Tumor, Cell Proliferation, Mice, Small Molecule Libraries
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