Targeting Krebs-cycle-deficient renal cell carcinoma with Poly ADP-ribose polymerase inhibitors and low-dose alkylating chemotherapy
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Daiki Ueno1,*, Juan C. Vasquez2,*, Amrita Sule3,*, Jiayu Liang4, Jinny van Doorn3, Ranjini Sundaram3, Sam Friedman3, Randy Caliliw1, Shinji Ohtake1, Xun Bao5, Jing Li5, Huihui Ye6, Karla Boyd2, Rong Rong Huang6, Jack Dodson7, Paul Boutros7, Ranjit S. Bindra3,# and Brian Shuch1,#
1 Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
2 Section of Pediatric Hematology and Oncology, Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06510, USA
3 Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06510, USA
4 Department of Urology, West China Hospital/School of Medicine, Chengdu City, Sichuan Province, PR China
5 Karmanos Cancer Institute, Wayne State University, Detroit, MI 48202, USA
6 Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095, USA
7 Department of Human Genetics, University of California, Los Angeles, CA 90095, USA
* These authors contributed equally to this work
# These authors jointly supervised this work
|Ranjit S. Bindra,||email:||[email protected]|
|Brian Shuch,||email:||[email protected]|
Keywords: FH; SDHB; renal cell carcinoma; PARP inhibitor; temozolomide
Received: June 01, 2022 Accepted: August 29, 2022 Published: September 14, 2022
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 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). 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.
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