Hoerner Christian R, Chen Viola J, Fan Alice C
Division of Oncology, Department of Medicine, Stanford University School of Medicine, CA, USA.
Kidney Cancer. 2019 Feb 5;3(1):15-29. doi: 10.3233/KCA-180043.
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.
癌症的一个重要标志是“代谢重编程”，即细胞代谢的重新布线以支持细胞快速增殖[1-5]。通过致癌代谢物介导的转化或肾细胞癌（RCC）中癌基因的激活进行的代谢重编程，全面影响RCC细胞中的能量产生以及葡萄糖和谷氨酰胺的利用，这可促进对谷氨酰胺供应的依赖以支持细胞生长和增殖[6,7]。谷氨酰胺酶是谷氨酰胺代谢中的关键酶，新型谷氨酰胺酶抑制剂将谷氨酰胺成瘾作为转移性RCC（mRCC）的一种可行治疗策略。在此，我们综述谷氨酰胺代谢途径以及细胞谷氨酰胺利用的变化如何促进RCC的进展。这一概述为在mRCC患者中靶向该途径提供了科学依据。我们将总结目前对RCC中谷氨酰胺酶抑制剂抗肿瘤疗效的细胞和分子机制的理解，概述在mRCC中靶向谷氨酰胺酶的临床研究，并综述识别用于患者分层的生物标志物以及在使用这类新型抗癌药物治疗的患者中早期检测治疗反应的方法。最终，正在进行的临床试验结果将证明谷氨酰胺酶抑制是否可成为目前用于mRCC患者的药物库中的一项有价值补充。
