Department of Oncology, University of Oxford, Oxford, United Kingdom.
Artios Pharma, Babraham Research Campus, Cambridge, United Kingdom.
Clin Cancer Res. 2023 Apr 14;29(8):1631-1642. doi: 10.1158/1078-0432.CCR-22-2977.
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.
We characterized the response to Polθ inhibition in combination with ionizing radiation in different cancer cell models in vitro and in vivo.
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, 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.
These results pave the way for future clinical trials of Polθ inhibitors in combination with radiotherapy.
DNA 聚合酶θ（Polθ，由 POLQ 基因编码）是一种对微同源介导末端连接（MMEJ）至关重要的 DNA 修复酶。Polθ 在正常组织中的表达有限，但在癌细胞中经常过表达，因此代表了肿瘤特异性放射增敏的理想靶点。在这项研究中，我们评估了用新型小分子抑制剂靶向 Polθ 是否是提高放射治疗效果的可行策略。
我们在体外和体内不同的癌细胞模型中研究了 Polθ 抑制与电离辐射联合的反应。
在这里，我们表明，ART558 和 ART899 是 Polθ DNA 聚合酶结构域的两种新型特异性别构抑制剂，能够有效地增敏肿瘤细胞，尤其是与分次放疗联合使用时。重要的是，非癌细胞不会因 Polθ 抑制而增敏。从机制上讲，我们表明 Polθ 抑制引起的放射增敏在复制细胞中最有效，并且是由于 DNA 损伤修复受损所致。我们还表明，在缺氧条件下，放射增敏仍然有效，这表明这些抑制剂可能有助于克服缺氧诱导的放射抗性。此外，我们首次描述了 ART899 并将其描述为一种具有改善代谢稳定性的有效且特异性的 Polθ 抑制剂。在体内，使用 ART899 抑制 Polθ 与分次放疗的组合具有良好的耐受性，与单独放疗相比，肿瘤生长明显减少。
这些结果为未来将 Polθ 抑制剂与放射疗法联合进行临床试验铺平了道路。
