Metabolic reprogramming in clear cell renal cell carcinoma

Key Points The incidence of kidney cancer, particularly clear cell renal cell carcinoma, is increasing and knowledge of its pathophysiology is essential for nephrologists Reprogramming of metabolic pathways enables cancer cells to rapidly proliferate, survive in conditions of nutrient depletion and hypoxia, and evade the immune system Most forms of kidney cancer are associated with reprogramming of metabolic pathways including oxygen sensing, the tricarboxylic acid cycle and the metabolism of tryptophan, fatty acids, glucose, glutamine and arginine Metabolic reprogramming provides opportunities for functional imaging approaches based on the altered pathways Novel therapies for kidney cancers that target critical proteins or enzymes that are involved in dysregulated metabolic pathways are being developed Clear cell renal cell carcinoma is associated with reprogramming of metabolic pathways including glucose and fatty acid metabolism and the tricarboxylic acid cycle. Here, the authors discuss these reprogrammed pathways and the opportunities they provide for new therapies, imaging modalities and biomarkers. Research in many cancers has uncovered changes in metabolic pathways that control tumour energetics and biosynthesis, so-called metabolic reprogramming. Studies in clear cell renal cell carcinoma (ccRCC) have been particularly revealing, leading to the concept that ccRCC is a metabolic disease. ccRCC is generally accompanied by reprogramming of glucose and fatty acid metabolism and of the tricarboxylic acid cycle. Metabolism of tryptophan, arginine and glutamine is also reprogrammed in many ccRCCs, and these changes provide opportunities for new therapeutic strategies, biomarkers and imaging modalities. In particular, metabolic reprogramming facilitates the identification of novel and repurposed drugs that could potentially be used to treat ccRCC, which when metastatic has currently limited long-term treatment options. Further research and dissemination of these concepts to nephrologists and oncologists will lead to clinical trials of therapeutics specifically targeted to tumour metabolism, rather than generally toxic to all proliferating cells. Such novel agents are highly likely to be more effective and to have far fewer adverse effects than existing drugs.