Fig. 3: Therapeutic intervention for HLRCC patients.

Given the control that FH loss and fumarate accumulation exert on several oncogenic factors, multiple inhibitors are being or could expect to be used in clinical interventions. For instance, PI3K cascade activation can be targeted using Sunitinib and the downstream effects of it using AKT inhibitors. Moreover, AMPK is re-activated through metformin treatment, indirectly inhibiting mTOR activation. Still, metformin could affect the complex I in the electron transport chain. As FH deficiency leads to decreased oxidative phosphorylation (OXPHOS), it is unclear whether this treatment could be beneficial. Beyond metformin, mTOR activation could be targeted by ABL1 inhibitors. Metabolically, these tumours could benefit from HMOX1 inhibition using zinc protophorphyrin (ZnPP) or an imidazole-based inhibitor SLV-11199, and LDHA inhibitors affecting the glycolytic flux. In addition, the inhibition of the purine salvage pathway using 6-mercaptopurine (6-MP) has been shown to affect the viability of FH-deficient cells. Furthermore, several anti-angiogenic therapies based on VEGF and EGFR inhibition are currently being used in the clinic. Interestingly, the new results highlighting the role of MYC activation in these tumours could open new therapeutic strategies based on a novel MYC inhibitor, omomyc. Finally, given the alterations occurring in the epigenetic machinery in FH-deficient tumours, inhibitors of DNA methyltransferases (DNMTs) are being tested in clinical trials. PI3K Phosphatidylinositol-3-kinase, AKT AKT Serine/Threonine Kinase 1, ABL1 ABL Proto-Oncogene 1, mTOR mammalian target of rapamycin, AMPK AMP-activated Protein Kinase, PTEN Phosphatase and tensin homolog, HMOX1 Heme Oxygenase 1, VEGF Vascular Endothelial Factor, LDHA Lactate Dehydrogenase A, EGFR Epidermal Growth Factor Receptor, 2SC 2-succinic-cysteine, CI-V Electron transport chain Complex I–V, HIF1A Hypoxia Inducible Factor A, PHD Prolyl hydroxylase.