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

Abstract

// Daiki Ueno 1 , * , Juan C. Vasquez 2 , * , Amrita Sule 3 , * , Jiayu Liang 4 , Jinny van Doorn 3 , Ranjini Sundaram 3 , Sam Friedman 3 , Randy Caliliw 1 , Shinji Ohtake 1 , Xun Bao 5 , Jing Li 5 , Huihui Ye 6 , Karla Boyd 2 , Rong Rong Huang 6 , Jack Dodson 7 , Paul Boutros 7 , Ranjit S. Bindra 3 , # and Brian Shuch 1 , # 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 Correspondence to: 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 Copyright: © 2022 Ueno et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT 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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