| 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
|
| リソース情報 |
| ヒト・動物細胞 |
KP4(RCB1005)
EBC-1(RCB1965) |
