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1. Ribonucleotide reductase inhibitors suppress SAMHD1 ara‐CTPase activity enhancing cytarabine efficacy

Author

Sean G Rudd, Nikolaos Tsesmetzis, Kumar Sanjiv, Cynthia BJ Paulin, Lakshmi Sandhow, Juliane Kutzner, Ida Hed Myrberg, Sarah S Bunten, Hanna Axelsson, Si Min Zhang, Azita Rasti, Petri Mäkelä, Si'Ana A Coggins, Sijia Tao, Sharda Suman, Rui M Branca, Georgios Mermelekas, Elisée Wiita, Sun Lee, Julian Walfridsson, Raymond F Schinazi, Baek Kim, Janne Lehtiö, Georgios Z Rassidakis, Katja Pokrovskaja Tamm, Ulrika Warpman‐Berglund, Mats Heyman, Dan Grandér, Sören Lehmann, Thomas Lundbäck, Hong Qian, Jan‐Inge Henter, Torsten Schaller, Thomas Helleday, and Nikolas Herold

Subjects
acute myeloid leukaemia, chemotherapy resistance, drug synergy, precision medicine, SAMHD1, Medicine (General), R5-920, Genetics, QH426-470
Abstract

Abstract The deoxycytidine analogue cytarabine (ara‐C) remains the backbone treatment of acute myeloid leukaemia (AML) as well as other haematological and lymphoid malignancies, but must be combined with other chemotherapeutics to achieve cure. Yet, the underlying mechanism dictating synergistic efficacy of combination chemotherapy remains largely unknown. The dNTPase SAMHD1, which regulates dNTP homoeostasis antagonistically to ribonucleotide reductase (RNR), limits ara‐C efficacy by hydrolysing the active triphosphate metabolite ara‐CTP. Here, we report that clinically used inhibitors of RNR, such as gemcitabine and hydroxyurea, overcome the SAMHD1‐mediated barrier to ara‐C efficacy in primary blasts and mouse models of AML, displaying SAMHD1‐dependent synergy with ara‐C. We present evidence that this is mediated by dNTP pool imbalances leading to allosteric reduction of SAMHD1 ara‐CTPase activity. Thus, SAMHD1 constitutes a novel biomarker for combination therapies of ara‐C and RNR inhibitors with immediate consequences for clinical practice to improve treatment of AML.

Published
2020
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2. Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells

Author

Sean G. Rudd, Shruti Regmi, Roni H. G. Wright, Evert Homan, Olga Loseva, Thomas Helleday, Sabin Llona-Minguez, Olov A. Wallner, Ingrid Almlöf, Anna-Lena Gustavsson, Jofre Font-Mateu, Rebecka Isaksson, Megan Carter, Ann-Sofie Jemth, Pål Stenmark, Thomas Lundbäck, Helena Almqvist, Pawel Baranczewski, Kia Strömberg, Nicholas C.K. Valerie, Brent D. G. Page, Martin Scobie, Fredrik Jeppsson, Hanna Axelsson, and Miguel Beato

Subjects
0301 basic medicine, Medicin och hälsovetenskap, Science, General Physics and Astronomy, 616.2, Drug development, Biology, Medical and Health Sciences, Article, General Biochemistry, Genetics and Molecular Biology, Chromatin remodeling, Fàrmacs, Target validation, 03 medical and health sciences, chemistry.chemical_compound, Breast cancer, RNA interference, medicine, Drug discovery and development, lcsh:Science, Regulation of gene expression, chemistry.chemical_classification, Multidisciplinary, Cáncer de pulmón, 030102 biochemistry & molecular biology, Cell growth, Drugs, General Chemistry, Desarrollo de fármacos, 3. Good health, Cell nucleus, 030104 developmental biology, medicine.anatomical_structure, Enzyme, chemistry, Desenvolupament de fàrmacs, Fármacos, Cancer research, Screening, Càncer de pulmó, lcsh:Q, Signal transduction, Lung cancer, Adenosine triphosphate
Abstract

With a diverse network of substrates, NUDIX hydrolases have emerged as a key family of nucleotide-metabolizing enzymes. NUDT5 (also called NUDIX5) has been implicated in ADP-ribose and 8-oxo-guanine metabolism and was recently identified as a rheostat of hormone-dependent gene regulation and proliferation in breast cancer cells. Here, we further elucidate the physiological relevance of known NUDT5 substrates and underscore the biological requirement for NUDT5 in gene regulation and proliferation of breast cancer cells. We confirm the involvement of NUDT5 in ADP-ribose metabolism and dissociate a relationship to oxidized nucleotide sanitation. Furthermore, we identify potent NUDT5 inhibitors, which are optimized to promote maximal NUDT5 cellular target engagement by CETSA. Lead compound, TH5427, blocks progestin-dependent, PAR-derived nuclear ATP synthesis and subsequent chromatin remodeling, gene regulation and proliferation in breast cancer cells. We herein present TH5427 as a promising, targeted inhibitor that can be used to further study NUDT5 activity and ADP-ribose metabolism., NUDIX hydrolases are an important family of nucleotide-metabolizing enzymes. Here, the authors identify potent, small molecule inhibitors of NUDT5, which is implicated in ADP-ribose and 8-oxo-guanine metabolism, and confirm its role in gene regulation and proliferation in breast cancer cells.

Published
2018

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