Data from Small-Molecule Polθ Inhibitors Provide Safe and Effective Tumor Radiosensitization in Preclinical Models

• DOI: 10.1158/1078-0432.c.6533180.v1
• Publication Date: 2023-04-01T05:50:14Z
• Authors: Gonzalo Rodriguez...; 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 B. Majithiya; Desiree Piscitello; Eeson Rajendra; Martin L. Stockley; Simon J. Boulton; Ester M. Hammond; Robert A. Heald; Graeme C.M. Smith; Helen M.R. Robinson; Geoff S. Higgins
• Keywords: Radioresistance

<div>AbstractPurpose:<p>DNA polymerase theta (Polθ) is a DNA repair enzyme critical for microhomology mediated end joining (MMEJ). Polθ has limited expression in normal tissues but frequently overexpressed cancer cells and, therefore, represents an ideal target tumor-specific radiosensitization. In this study we evaluate whether targeting with novel small-molecule inhibitors feasible strategy to improve the efficacy of radiotherapy.</p>Experimental design:<p>We characterized response inhibition combination ionizing radiation different cell models <i>in vitro</i> and vivo</i>.</p>Results:<p>Here, show that ART558 ART899, two specific allosteric domain, potently radiosensitize tumor cells, particularly when combined fractionated radiation. Importantly, noncancerous were not radiosensitized by inhibition. Mechanistically, radiosensitization caused most effective replicating due impaired damage repair. We also still under hypoxia, suggesting these may help overcome hypoxia-induced radioresistance. addition, describe first time ART899 characterize it as potent inhibitor improved metabolic stability. <i>In vivo</i>, using well tolerated results significant reduction growth compared alone.</p>Conclusions:<p>These pave way future clinical trials radiotherapy.</p></div>