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A Novel Dual ATM/DNA-PK Inhibitor, XRD-0394, Potently Radiosensitizes and Potentiates PARP and Topoisomerase I Inhibitors.

Publication ,  Journal Article
Gilmer, TM; Lai, C-H; Guo, K; Deland, K; Ashcraft, KA; Stewart, AE; Wang, Y; Fu, J; Wood, KC; Kirsch, DG; Kastan, MB
Published in: Mol Cancer Ther
June 4, 2024

A majority of patients with cancer receive radiotherapy 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 radiotherapy 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. In addition, 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 radiotherapy has completed. These results provide a rationale for future clinical trials with XRD-0394 in combination with radiotherapy, PARP inhibitors, and targeted delivery of topoisomerase I inhibitors.

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Published In

Mol Cancer Ther

DOI

EISSN

1538-8514

Publication Date

June 4, 2024

Volume

23

Issue

6

Start / End Page

751 / 765

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Topoisomerase I Inhibitors
  • Radiation-Sensitizing Agents
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Oncology & Carcinogenesis
  • Mice
  • Humans
  • Female
  • Drug Synergism
  • DNA-Activated Protein Kinase
 

Citation

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Gilmer, T. M., Lai, C.-H., Guo, K., Deland, K., Ashcraft, K. A., Stewart, A. E., … Kastan, M. B. (2024). A Novel Dual ATM/DNA-PK Inhibitor, XRD-0394, Potently Radiosensitizes and Potentiates PARP and Topoisomerase I Inhibitors. Mol Cancer Ther, 23(6), 751–765. https://doi.org/10.1158/1535-7163.MCT-23-0890
Gilmer, Tona M., Chun-Hsiang Lai, Kexiao Guo, Katherine Deland, Kathleen A. Ashcraft, Amy E. Stewart, Yaode Wang, et al. “A Novel Dual ATM/DNA-PK Inhibitor, XRD-0394, Potently Radiosensitizes and Potentiates PARP and Topoisomerase I Inhibitors.Mol Cancer Ther 23, no. 6 (June 4, 2024): 751–65. https://doi.org/10.1158/1535-7163.MCT-23-0890.
Gilmer TM, Lai C-H, Guo K, Deland K, Ashcraft KA, Stewart AE, et al. A Novel Dual ATM/DNA-PK Inhibitor, XRD-0394, Potently Radiosensitizes and Potentiates PARP and Topoisomerase I Inhibitors. Mol Cancer Ther. 2024 Jun 4;23(6):751–65.
Gilmer, Tona M., et al. “A Novel Dual ATM/DNA-PK Inhibitor, XRD-0394, Potently Radiosensitizes and Potentiates PARP and Topoisomerase I Inhibitors.Mol Cancer Ther, vol. 23, no. 6, June 2024, pp. 751–65. Pubmed, doi:10.1158/1535-7163.MCT-23-0890.
Gilmer TM, Lai C-H, Guo K, Deland K, Ashcraft KA, Stewart AE, Wang Y, Fu J, Wood KC, Kirsch DG, Kastan MB. A Novel Dual ATM/DNA-PK Inhibitor, XRD-0394, Potently Radiosensitizes and Potentiates PARP and Topoisomerase I Inhibitors. Mol Cancer Ther. 2024 Jun 4;23(6):751–765.

Published In

Mol Cancer Ther

DOI

EISSN

1538-8514

Publication Date

June 4, 2024

Volume

23

Issue

6

Start / End Page

751 / 765

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Topoisomerase I Inhibitors
  • Radiation-Sensitizing Agents
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Oncology & Carcinogenesis
  • Mice
  • Humans
  • Female
  • Drug Synergism
  • DNA-Activated Protein Kinase