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

ABSTRACT:

Purpose

DNA polymerase theta (Polθ, encoded by the POLQ gene) 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 this 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

SUBMITTER: Rodriguez-Berriguete G 

PROVIDER: S-EPMC10102842 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature