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Raczka et al. Cancer Drug Resist 2019;2:356-64 Cancer
DOI: 10.20517/cdr.2018.004 Drug Resistance

Opinion Open Access

Glutaminase inhibition in renal cell carcinoma
therapy

Aleksandra M. Raczka , Paul A. Reynolds 1,2
1,2
1 School of Medicine, University of St Andrews, St Andrews KY16 9TF, UK.
2 Biomedical Sciences Research Complex, University of St Andrews, St Andrews, UK.

Correspondence to: Dr. Paul Reynolds, School of Medicine, University of St. Andrews, St. Andrews KY16 9TF, UK.
E-mail: par10@st-andrews.ac.uk

How to cite this article: Raczka AM, Reynolds PA. Glutaminase inhibition in renal cell carcinoma therapy. Cancer Drug Resist
2019;2:356-64. http://dx.doi.org/10.20517/cdr.2018.004
Received: 14 Dec 2018 First Decision: 29 Mar 2019 Revised: 1 Apr 2019 Accepted: 8 Apr 2019 Published: 19 Jun 2019

Science Editor: Martin Michaelis Copy Editor: Cai-Hong Wang Production Editor: Huan-Liang Wu

Abstract
Receptor tyrosine kinase inhibitors have been a standard first-line therapy for renal cell carcinoma (RCC) for over a
decade. Although they stabilize the disease, they are unable to remove all tumor cells, leading to relapse. Moreover,
both intrinsic and acquired resistance to therapy are a significant health burden. In order to overcome resistance,
several combination therapies have been recently approved by the FDA. Another approach takes advantage of altered
metabolism in tumor cells, which switch to alternative metabolic pathways to sustain their rapid growth and proliferation.
CB-839 is a small molecule inhibitor of kidney type glutaminase (GLS). GLS is often upregulated in glutamine addicted
cancers, enhancing glutamine metabolism for the production of energy and the biosynthesis of various cellular building
blocks. CB-839 is currently in clinical trials for several tumors, including clear cell (cc)RCC, both as monotherapy and in
combination with the approved therapeutic agents everolimus, cabozantinib and nivolumab. Early results of Phase 1/2
clinical trials look promising, especially for CB-839 plus cabozantinib, and all combinations seem to be well tolerated.
However, cancer cells can activate compensatory pathways to overcome glutaminolysis inhibition. Therefore, genetic
and metabolomic studies are crucial for the successful implementation of CB-839 alone or in combination in subgroups
of ccRCC patients.

Keywords: Glutamine addiction, renal cell carcinoma, combination therapy, metabolism

INTRODUCTION
Renal cell carcinoma (RCC) represents 90% of kidney cancers and 2%-3% of all malignancies. It remains
the deadliest genitourinary malignancy, with a new case count globally of approximately 270,000 and

© The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0
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