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.