Targeting PFKFB3 radiosensitizes cancer cells and suppresses homologous recombination

Nina M. S. Gustafsson (), Katarina Färnegårdh, Nadilly Bonagas, Anna Huguet Ninou, Petra Groth, Elisee Wiita, Mattias Jönsson, Kenth Hallberg, Jemina Lehto, Rosa Pennisi, Jessica Martinsson, Carina Norström, Jessica Hollers, Johan Schultz, Martin Andersson, Natalia Markova, Petra Marttila, Baek Kim, Martin Norin, Thomas Olin and Thomas Helleday ()
Additional contact information
Nina M. S. Gustafsson: Karolinska Institutet
Katarina Färnegårdh: Karolinska Science Park
Nadilly Bonagas: Karolinska Institutet
Anna Huguet Ninou: Karolinska Institutet
Petra Groth: Karolinska Institutet
Elisee Wiita: Karolinska Institutet
Mattias Jönsson: Karolinska Science Park
Kenth Hallberg: SARomics Biostructures AB
Jemina Lehto: Karolinska Institutet
Rosa Pennisi: Roma Tre University
Jessica Martinsson: Sprint Bioscience
Carina Norström: Karolinska Science Park
Jessica Hollers: Emory University School of Medicine
Johan Schultz: Karolinska Science Park
Martin Andersson: Sprint Bioscience
Natalia Markova: Malvern Instruments
Petra Marttila: Karolinska Institutet
Baek Kim: Emory University School of Medicine
Martin Norin: Karolinska Science Park
Thomas Olin: Karolinska Science Park
Thomas Helleday: Karolinska Institutet

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06287-x

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