Targeting PFKFB3 radiosensitizes cancer cells and suppresses homologous recombination

• Type of Material: Article
• Authors: Nina M. S. Gustafsson, Karolinska Institutet; Katarina Farnegardh, Kancera AB; Nadilly Bonagas, Karolinska Institutet; Anna Huguet Ninou, Karolinska Institutet; Petra Groth, Karolinska Institutet; Elisee Wiita, Karolinska Institutet; Mattias Jonsson, Kancera AB; Kenth Hallberg, SARom Biostruct AB; Jemina Lehto, Karolinska Institutet; Rosa Pennisi, Roma Tre University; Jessica Martinsson, Sprint Bioscience; Carina Norstrom, Kancera AB; Jessica Hollers, Emory University; Johan Schultz, Kancera AB; Martin Andersson, Sprint Bioscience; Natalia Markova, Malvern Instruments; Petra Marttila, Karolinska Institutet; Baek Kim, Emory University; Martin Norin, Kancera AB; Thomas Olin, Kancera AB; Thomas Helleday, Karolinska Institutet
• Language: English
• Date: 2018-09-24
• Publisher: Nature Research (part of Springer Nature): Fully open access journals
• Publication Version: Final Published Version
• Copyright Statement: © 2018, The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-018-06287-x
• Title of Journal or Parent Work: Nature Communications
• ISSN: 2041-1723
• Volume: 9
• Issue: 1
• Start Page: 3872
• End Page: 3872
• Grant/Funding Information: This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement no. 722729 (A.H.N. and J.L.), the Karolinska Institutet’s KID-funding for doctoral students (N.B.), the Swedish Society for Medical Research (N.G.), the NIH Research Project Grant Programs R01 GM104198 and R01 AI136581 (J.H. and B.K.), the Swedish Research Council, the European Research Council, the Swedish Cancer Society and the Torsten and Ragnar Söderberg Foundation (all T.H.), and the Helleday Foundation (P.M., N.B., and P.G.).
• Keywords: GENOME INTEGRITY; Science & Technology; DNA-DAMAGE RESPONSE; Science & Technology - Other Topics; 6-PHOSPHOFRUCTO-2-KINASE PFKFB3; RIBONUCLEOTIDE REDUCTASE; IN-VITRO; Multidisciplinary Sciences; DNTP POOLS; REPAIR; DOUBLE-STRAND BREAKS; THERMAL SHIFT ASSAY; GLUCOSE-METABOLISM
• Research Categories: Health Sciences, Oncology; Health Sciences, Pathology

Abstract

The glycolytic PFKFB3 enzyme is widely overexpressed in cancer cells and an emerging anti-cancer target. Here, we identify PFKFB3 as a critical factor in homologous recombination (HR) repair of DNA double-strand breaks. PFKFB3 rapidly relocates into ionizing radiation (IR)-induced nuclear foci in an MRN-ATM-γH2AX-MDC1-dependent manner and co-localizes with DNA damage and HR repair proteins. PFKFB3 relocalization is critical for recruitment of HR proteins, HR activity, and cell survival upon IR. We develop KAN0438757, a small molecule inhibitor that potently targets PFKFB3. Pharmacological PFKFB3 inhibition impairs recruitment of ribonucleotide reductase M2 and deoxynucleotide incorporation upon DNA repair, and reduces dNTP levels. Importantly, KAN0438757 induces radiosensitization in transformed cells while leaving non-transformed cells unaffected. In summary, we identify a key role for PFKFB3 enzymatic activity in HR repair and present KAN0438757, a selective PFKFB3 inhibitor that could potentially be used as a strategy for the treatment of cancer.