The ‘Achilles Heel’ of Metabolism in Renal Cell Carcinoma: Glutaminase Inhibition as a Rational Treatment Strategy
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An important hallmark of cancer is ‘metabolic reprogramming’ or the rewiring of cellular metabolism to support rapid cell proliferation [ 1 – 5 ]. Metabolic reprogramming through oncometabolite-mediated transformation or activation of oncogenes in renal cell carcinoma (RCC) globally impacts energy production as well as glucose and glutamine utilization in RCC cells, which can promote dependence on glutamine supply to support cell growth and proliferation [ 6 , 7 ]. Novel inhibitors of glutaminase, a key enzyme in glutamine metabolism, target glutamine addiction as a viable treatment strategy in metastatic RCC (mRCC). Here, we review glutamine metabolic pathways and how changes in cellular glutamine utilization enable the progression of RCC. This overview provides scientific rationale for targeting this pathway in patients with mRCC. We will summarize the current understanding of cellular and molecular mechanisms underlying anti-tumor efficacy of glutaminase inhibitors in RCC, provide an overview of clinical efforts targeting glutaminase in mRCC, and review approaches for identifying biomarkers for patient stratification and detecting therapeutic response early on in patients treated with this novel class of anti-cancer drug. Ultimately, results of ongoing clinical trials will demonstrate whether glutaminase inhibition can be a worthy addition to the current armamentarium of drugs used for patients with mRCC.
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CB-839, 968, and BPTES exhibit tumor-specific antiproliferative effects.
“Chemical agents targeting GLSs have been studied, and CB-839, 968, and BPTES have been found to exhibit tumor-specific antiproliferative effects199.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [199]
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- Authors
- Hoerner, C. R., Chen, V. J., & Fan, A. C.
- Affiliations
- Stanford Medicine (US)
- Corresponding author
- Fan, Alice C.
- Venue
- Kidney Cancer
- Publisher
- SAGE Publications
- Published
- 2019-01-25
- Volume
- 3
- Issue
- 1
- Pages
- 15-29
- ISSN
- 2468-4562 (ISSN-L)
- 2468-4570
- PMC
- PMC6400133
- OpenAlex
- W2914788991
- Cited by
- 68
- References
- 196
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 7 · 2023: 9 · 2022: 14 · 2021: 10 · 2020: 15 · 2019: 6
- FWCI
- 1.08
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- Locations
- Kidney Cancer (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Conquer Cancer Foundation
- Calithera Biosciences
- National Institutes of Health (T32 grant)
- National Cancer Institute (U54CA199075)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Renal cell carcinoma treatment
- Keywords
- renal cell carcinoma, metastatic renal cell carcinoma, glutaminase inhibition, glutamine metabolism, tumor metabolic reprogramming, glutamine addiction, oncometabolites, biomarkers, patient stratification, antitumor efficacy, targeted therapy
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