医学
癌症研究
PARP抑制剂
拓扑异构酶
药理学
放射治疗
体内
癌症
临床试验
体外
癌细胞
聚ADP核糖聚合酶
肿瘤科
内科学
DNA
化学
生物
生物化学
聚合酶
生物技术
作者
Tona M. Gilmer,Chun‐Hsiang Lai,Katie Guo,Katherine Deland,Kathleen A. Ashcraft,Amy E. Stewart,Yaode Wang,Ji-Yi Fu,Kris C. Wood,David G. Kirsch,Michael B. Kastan
出处
期刊:Molecular Cancer Therapeutics
[American Association for Cancer Research]
日期:2024-04-08
标识
DOI:10.1158/1535-7163.mct-23-0890
摘要
A majority of cancer patients receive radiation therapy as part of their treatment regimens whether using external beam therapy or locally-delivered radioisotopes. While often effective, some tumors are inadequately controlled with radiation and radiation therapy has significant short-term and long-term toxicities for cancer survivors. Insights into molecular mechanisms involved in cellular responses to DNA breaks introduced by radiation or other cancer therapies have been gained in recent years and approaches to manipulate these responses to enhance tumor cell killing or reduce normal tissue toxicity are of great interest. Here, we report the identification and initial characterization of XRD-0394, a potent and specific dual inhibitor of two DNA damage-response kinases, ATM and DNA-PKcs. This orally bioavailable molecule demonstrates significantly enhanced tumor cell kill in the setting of therapeutic ionizing irradiation in vitro and in vivo. XRD-0394 also potentiates the effectiveness of topoisomerase I inhibitors in vitro. Additionally, in cells lacking BRCA1/2 XRD-0394 shows single agent activity and synergy in combination with PARP inhibitors. A Phase Ia clinical trial (NCT05002140) with XRD-0394 in combination with RT has completed. These results provide a rationale for future clinical trials with XRD-0394 in combination with RT, PARP inhibitors and targeted delivery of topoisomerase I inhibitors.
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