Targeting metabolic and epigenetic reprogramming in metastatic fumarate hydratase-deficient renal cell carcinoma.

Abstract

Fumarate hydratase-deficient renal cell carcinoma (FHdRCC) has been classified under the new category of molecularly defined RCCs according to the WHO classification 2022. Although rare, FHdRCC is an aggressive malignancy with a high metastatic potential and poor prognosis, even at early stages. Due to its low incidence, no standard therapeutic regimen has been established to date. Several phase 2 clinical trials are evaluating combinations of targeted therapies in patients with advanced/metastatic disease. These include immune checkpoint inhibitors (nivolumab, tislelizumab, sintilimab, avelumab), multi-tyrosine kinase inhibitors (cabozantinib, erlotinib, lenvatinib, axitinib, vandetanib), and PARP inhibitors (talazoparib). The most promising combinations are nivolumab/cabozantinib (N = 5, objective response rate (ORR): 100%), lenvatinib/tislelizumab (N = 14, ORR: 93.3%), bevacizumab/erlotinib (N = 43, ORR: 72%), and sintilimab/axitinib (N = 19, ORR: 63.1%). In this review, we will provide a detailed overview of ongoing clinical trials, highlighting the roles of metabolic and epigenetic reprogramming, as well as pro- oncogenic signaling, which together form the backbone for emerging novel targeted treatment strategies. Targeting these specific signaling pathways will shift the therapeutic landscape toward personalized medicine in metastatic FHdRCC.