Small-molecule Polθ inhibitors provide safe and effective tumor radiosensitization in preclinical models
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Gonzalo Rodriguez-Berriguete Marco Ranzani Remko Prevo Rathi Puliyadi Nicole Machado Hannah R Bolland Val Millar Daniel Ebner Marie Boursier Aurora Cerutti Alessandro Cicconi Alessandro Galbiati Diego Grande Vera Grinkevich Jayesh Majithiya Desiree Piscitello Eeson Rajendra Martin L Stockley Simon Boulton Ester M Hammond Robert A Heald Graeme CM Smith Helen MR Robinson Geoff S HigginsAbstract
PURPOSE: DNA polymerase theta (Polθ) is a DNA repair enzyme critical for microhomology mediated end joining (MMEJ). Polθ has limited expression in normal tissues but is frequently overexpressed in cancer cells and, therefore, represents an ideal target for tumor-specific radiosensitization. In the present study we evaluate whether targeting Polθ with novel small-molecule inhibitors is a feasible strategy to improve the efficacy of radiotherapy. EXPERIMENTAL DESIGN: We characterized the response to Polθ inhibition in combination with ionizing radiation in different cancer cell models in vitro and in vivo. RESULTS: Here, we show that ART558 and ART899, two novel and specific allosteric inhibitors of the Polθ DNA polymerase domain, potently radiosensitize tumor cells, particularly when combined with fractionated radiation. Importantly, non-cancerous cells were not radiosensitized by Polθ inhibition. Mechanistically, we show that the radiosensitization caused by Polθ inhibition is most effective in replicating cells and is due to impaired DNA damage repair. We also show that radiosensitization is still effective under hypoxia, suggesting that these inhibitors may help overcome hypoxia-induced radioresistance. In addition, we describe for the first time ART899 and characterize it as a potent and specific Polθ inhibitor with improved metabolic stability. In vivo, the combination of Polθ inhibition using ART899 with fractionated radiation is well tolerated and results in a significant reduction in tumor growth compared to radiation alone. CONCLUSION: These results pave the way for future clinical trials of Polθ inhibitors in combination with radiotherapy.
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Journal Clinical cancer research
Volume 29
Issue number 8
Pages 1631-1642
Available online
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Publisher website (DOI) 10.1158/1078-0432.CCR-22-2977
Europe PubMed Central 36689546
Pubmed 36689546
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