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Oncotarget | Targeting Krebs-cycle-deficient RCC with Poly ADP-ribose Polymerase Inhibitors, Low-dose Alkylating Chemotherapy

“In this study, we sought to examine the activity of combined TMZ and PARPi in Krebs-cycle-deficient renal cancer models.”

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BUFFALO, NY- September 20, 2022 – A new research paper was published in Oncotarget’s Volume 13 on September 14, 2022, entitled, “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. 

Researchers Daiki Ueno, Juan C. Vasquez, Amrita Sule, Jiayu Liang, Jinny van Doorn, Ranjini Sundaram, Sam Friedman, Randy Caliliw, Shinji Ohtake, Xun Bao, Jing Li, Huihui Ye, Karla Boyd, Rong Rong Huang, Jack Dodson, Paul Boutros, Ranjit S. Bindra, and Brian Shuch from Yale University School of Medicine, West China Hospital/School of Medicine, Wayne State University, and University of California, Los Angeles have developed new syngeneic Fh1- and Sdhb-deficient murine models of RCC, which demonstrate the expected accumulation of fumarate and succinate, alterations in the transcriptomic and methylation profile, and an increase in unresolved DNA double-strand breaks (DSBs). 

“In this study, we sought to examine the activity of combined TMZ and PARPi in Krebs-cycle-deficient renal cancer models. Fh1 and Sdhb are the murine counter part of human FH and SDHB, respectively.”

The efficacy of poly ADP-ribose polymerase inhibitors (PARPis) and temozolomide (TMZ), alone and in combination, was evaluated both in vitro and in vivo. Combination treatment with PARPi and TMZ results in marked in vitro cytotoxicity in Fh1- and Sdhb-deficient cells. In vivo, treatment with standard dosing of the PARP inhibitor BGB-290 and low-dose TMZ significantly inhibits tumor growth without a significant increase in toxicity. 

These findings provide the basis for a novel therapeutic strategy exploiting HR deficiency in FH and SDH-deficient RCC with combined PARP inhibition and low-dose alkylating chemotherapy.

“Using newly developed Fh1 and Sdhb deficient syngeneic mouse models, we demonstrate that oncometabolite-induced HR defects can be leveraged with PARPi treatment to enhance sensitivity to low-dose TMZ in Krebs-cycle-deficient renal cancer.”

DOI: https://doi.org/10.18632/oncotarget.28273

Correspondence to: Ranjit S. Bindra & Brian Shuch – Emails: Ranjit.Bindra@yale.edu & bshuch@mednet.ucla.edu 

Keywords: FH, SDHB, renal cell carcinoma, PARP inhibitor, temozolomide

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