Targeting Krebs-cycle-deficient renal cell carcinoma with Poly ADP-Ribose Polymerase inhibitors and low-dose alkylating chemotherapy

Loss-of-function mutations in genes encoding the Krebs cycle enzymes Fumarate Hydratase (FH) and Succinate Dehydrogenase (SDH) induce accumulation of fumarate and succinate, respectively and predispose patients to hereditary cancer syndromes including the development of aggressive renal cell carcinoma (RCC). Fumarate and succinate competitively inhibit αKG-dependent dioxygenases, including Lysine-specific demethylase 4A/B (KDM4A/B), leading to suppression of the homologous recombination (HR) DNA repair pathway. In this study, we evaluated novel treatment approaches in newly generated models of FH- and SDHB-deficient RCC. CRISPR/Cas9 was used to engineer isogenic Fh1- and Sdhb-deficient murine models of RCC. The efficacy of poly ADP-ribose polymerase inhibitors (PARPis) and temozolomide (TMZ), alone and in combination, was evaluated both in vitroand in vivo.