論文 - 詳細
| RRC ID | 66858 |
|---|---|
| 著者 | Zenke FT, Zimmermann A, Sirrenberg C, Dahmen H, Kirkin V, Pehl U, Grombacher T, Wilm C, Fuchss T, Amendt C, Vassilev LT, Blaukat A. |
| タイトル | Pharmacologic Inhibitor of DNA-PK, M3814, Potentiates Radiotherapy and Regresses Human Tumors in Mouse Models. |
| ジャーナル | Mol Cancer Ther |
| Abstract |
Physical and chemical DNA-damaging agents are used widely in the treatment of cancer. Double-strand break (DSB) lesions in DNA are the most deleterious form of damage and, if left unrepaired, can effectively kill cancer cells. DNA-dependent protein kinase (DNA-PK) is a critical component of nonhomologous end joining (NHEJ), one of the two major pathways for DSB repair. Although DNA-PK has been considered an attractive target for cancer therapy, the development of pharmacologic DNA-PK inhibitors for clinical use has been lagging. Here, we report the discovery and characterization of a potent, selective, and orally bioavailable DNA-PK inhibitor, M3814 (peposertib), and provide in vivo proof of principle for DNA-PK inhibition as a novel approach to combination radiotherapy. M3814 potently inhibits DNA-PK catalytic activity and sensitizes multiple cancer cell lines to ionizing radiation (IR) and DSB-inducing agents. Inhibition of DNA-PK autophosphorylation in cancer cells or xenograft tumors led to an increased number of persistent DSBs. Oral administration of M3814 to two xenograft models of human cancer, using a clinically established 6-week fractionated radiation schedule, strongly potentiated the antitumor activity of IR and led to complete tumor regression at nontoxic doses. Our results strongly support DNA-PK inhibition as a novel approach for the combination radiotherapy of cancer. M3814 is currently under investigation in combination with radiotherapy in clinical trials. |
| 巻・号 | 19(5) |
| ページ | 1091-1101 |
| 公開日 | 2020-5-1 |
| DOI | 10.1158/1535-7163.MCT-19-0734 |
| PII | 1535-7163.MCT-19-0734 |
| PMID | 32220971 |
| MeSH | Animals Apoptosis Carcinoma, Non-Small-Cell Lung / drug therapy Carcinoma, Non-Small-Cell Lung / pathology Carcinoma, Non-Small-Cell Lung / radiotherapy* Cell Proliferation DNA-Activated Protein Kinase / antagonists & inhibitors* Female Gene Expression Regulation, Enzymologic / drug effects* Gene Expression Regulation, Neoplastic / drug effects* Head and Neck Neoplasms / drug therapy Head and Neck Neoplasms / pathology Head and Neck Neoplasms / radiotherapy* Humans Lung Neoplasms / drug therapy Lung Neoplasms / pathology Lung Neoplasms / radiotherapy Mice Mice, Nude Protein Kinase Inhibitors / pharmacology* Pyridazines / pharmacology* Quinazolines / pharmacology* Radiation, Ionizing* Squamous Cell Carcinoma of Head and Neck / drug therapy Squamous Cell Carcinoma of Head and Neck / pathology Squamous Cell Carcinoma of Head and Neck / radiotherapy Tumor Cells, Cultured Xenograft Model Antitumor Assays |
| IF | 5.615 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 9 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | KP4(RCB1005) EBC-1(RCB1965) |