ArticleClinical cancer research : an official journal of the American Association for Cancer Research2023
Small-Molecule Polθ Inhibitors Provide Safe and Effective Tumor Radiosensitization in Preclinical Models.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed.
- DNA polymerase theta (Polθ): a novel candidate for targeted cancer therapy.Cancer biology & therapy · 2026Review
- The Pharmacologic Profile of ART6043, a First-in-Class Clinical DNA Polymerase Theta Polymerase Domain Inhibitor Potentiating PARP Inhibitor Efficacy.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Article
- Article
- Emerging roles of POLR2L of RNA polymerase II dynamics and disease mechanisms (Review).Molecular medicine reports · 2026Review
- Loss of JAK1 Function Causes G2-M Cell-Cycle Defects Vulnerable to KIF18A Inhibition.Cancer research · 2026Article
- POLQ promotes tumor progression and immunosuppression via ATM‑P53 signaling in endometrial cancer.Oncology reports · 2026Article
- Precision-cut tumor slices: a biomimetic tool for accelerating oncological development from basic research to clinical translation.Frontiers in physiology · 2026Review
- POLQ and DNA-PK inhibition in muscle-invasive bladder cancer : Enhancing radiosensitivity with novel DNA damage response inhibitors to improve radiotherapy outcomes.Pathologie (Heidelberg, Germany) · 2026Article
- Repurposing clinically safe drugs for DNA repair pathway choice in CRISPR genome editing and synthetic lethality.Nature communications · 2025Article
- Search-and-remove genome editing allows selection of cells by DNA sequence.Nature communications · 2025Article
- Emerging insights into alternative end‑joining: Mechanisms, genome instability and therapeutic opportunities in cancer (Review).International journal of oncology · 2025Review
- RTx-303, an Orally Bioavailable Polθ Polymerase Inhibitor That Potentiates PARP Inhibitors in BRCA Mutant Tumors.Journal of medicinal chemistry · 2025Article
- Targeting DNA Damage Repair Pathways Beyond PARP Inhibition.Targeted oncology · 2025Review
- Polymerase theta inhibition impairs tumor growth and amplifies melphalan-induced DNA damage in multiple myeloma.Journal of translational medicine · 2025Article
- Polymerase Ѳ inhibitors combinations with approved and investigational agents in patient-derived tumor multi-cell type (mct) spheroids.Experimental and molecular pathology · 2025Article
- Unveiling new therapeutic targets for esophageal cancer treatment through single-cell transcriptomics: pH-responsive nanobubbles enhance the efficacy of 125I radiotherapy.Journal of nanobiotechnology · 2025Article
- Division of labor within polymerase theta in repair of CRISPR-induced DNA breaks inPNAS nexus · 2025Article
- Retrospective analysis and IMRT replanning of a 3D-CRT murine dose painting study for preclinical oxygen-guided radiotherapy.Scientific reports · 2025Article
- Targeting the DNA damage response in cancer.MedComm · 2024Review
- Polθ: emerging synthetic lethal partner in homologous recombination-deficient tumors.Cancer gene therapy · 2024Review
Corrections and comments
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Authors and funding
24 authors.
Funding
Abstract
purposeDNA 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
designWe characterized the response to Polθ inhibition in combination with ionizing radiation in different cancer cell models in vitro and in vivo.
resultsHere, 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, noncancerous 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 with radiation alone.
conclusionsThese results pave the way for future clinical trials of Polθ inhibitors in combination with radiotherapy.
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