Targeting strategies in the treatment of fumarate hydratase deficient renal cell carcinoma

Abstract

Fumarate hydratase (FH) - deficient renal cell carcinoma (FHdRCC) is a rare aggressive subtype of RCC caused by a germline or sporadic loss-of-function mutation in the FH gene. Here, we summarize how FH deficiency results in the accumulation of fumarate, which in turn leads to activation of hypoxia-inducible factor (HIF) through inhibition of prolyl hydroxylases. HIF promotes tumorigenesis by orchestrating a metabolic switch to glycolysis even under normoxia, a phenomenon well-known as the Warburg effect. HIF activates the transcription of many genes, including vascular endothelial growth factor (VEGF). Crosstalk between HIF and epidermal growth factor receptor (EGFR) has also been described as a tumor-promoting mechanism. In this review we discuss therapeutic options for FHdRCC with a focus on anti-angiogenesis and EGFR-blockade. We also address potential targets that arise within the metabolic escape routes taken by FH-deficient cells for cell growth and survival.

Keywords: bevacizumab; erlotinib; fumarate hydratase; fumarate hydratase deficient renal cell carcinoma; glucose; hereditary leiomyomatosis and renal cell cancer; metabolism; renal cell carcinoma (RCC).

Figure 1

Metabolic changes, signalling pathway alterations and therapeutic targets in FHdRCC. (A) Metabolic changes in FH deficiency: in the glycolytic pathway, glucose is converted to pyruvate by glycolysis (GLY), which can enter the mitochondria and fuel the tricarboxylic acid cycle (TCA) cycle, also known as citrate as well as Krebs cycle. Succinate dehydrogenase (SDH) generates fumarate and fumarate hydratase (FH) catalyzes the stereospecific hydration of fumarate to form L-malate. Glutaminase (GLS) breaks down glutamine to form glutamate, which is further converted to α-ketoglutarate and feeds the TCA cycle. In the urea cycle, argininosuccinate is cleaved by argininosuccinase (ASL), producing additional fumarate. This step can be reversed by the argininosuccinase synthase (ASS) if argininosuccinate is required (27). In FH deficiency, fumarate accumulating in the mitochondria can leak out to the cytosol and become an ‘oncometabolite’. (B) Fumarate-induced activation of signalling pathways: cytosolic fumarate, like succinate, inhibits a family of prolyl hydroxylases (PHDs), which under normoxia destabilize hypoxia-inducible factor (HIF) through hydroxylation of prolyl residues. Fumarate (and succinate)-induced PHD inhibition causes HIF-1α accumulation. In the nucleus, HIF-1α activates the transcription of target genes including vascular endothelial growth factor (VEGF) and glycolytic genes, initiating the metabolic shift known as the Warburg effect (left panel). Fumarate and succinate accumulation can also act as α-ketoglutarate (α-KG) antagonist, inhibiting α-KG-dependent dioxygenases. Thus, histone de-methylation process catalyzed by histone demethylases (KDM) is inhibited. Consecutively, epigenetic alterations including hypermethylation at histone markers H3K9 and HRK27 inhibit tumor suppressor genes resulting in tumor progression, drug resistance and cell dedifferentiation (31, mid panel). In a non-enzymatic process, high concentrations of fumarate can also lead to the succination of cysteine residues of Kelch-like ECH-associated protein 1 (KEAP1), which thus loses its ability to prevent nuclear factor (erythroid-derived 2)-like 2 (NRF2)-mediated antioxidant responses (right panel). In FHdRCC, NRF2 activation is protumorigenic. (C) Targeting strategies for FHdRCC: fumarate-induced HIF activation promotes tumor angiogenesis and proliferation through VEGF signalling, suggesting the use of bevacizumab to neutralize VEGF. Activation of the epidermal growth factor receptor (EGFR), a frequent event in many tumors, can also activate HIF-1α, and HIF-1α induced VEGF can contribute to the resistance against EGFR inhibitor such as erlotinib. This has led to bevacizumab plus erlotinib combination therapy in certain cancer types including FHdRCC. The metabolic shift arising from FH deficiency results in decreased levels of adenosine monophosphate (AMP)-activated protein kinase (AMPK) and, as a consequence, of the tumor suppressor p53. Raising the activity of AMPK again may therefore also be desirable in FHdRCC, which can be achieved using metformin, an indirect AMPK activator (49). In addition, targeting the metabolic escape routes of FH-deficient cells through inhibitors of heme biosynthesis and degradation would be attractive in the treatment of FHdRCC (26). Given the strict arginine dependence of FH-deficient tumor cells arginine deprivation (27) and de-methylating agents (32) according to DNA CGI hypermethylation phenotype might be a therapy-supporting concept.