Pharmacologic Inhibitor of DNA-PK, M3814, Potentiates Radiotherapy and Regresses Human Tumors in Mouse Models.
View/ Open
Date
2020-05-01ICR Author
Author
Zenke, FT
Zimmermann, A
Sirrenberg, C
Dahmen, H
Kirkin, V
Pehl, U
Grombacher, T
Wilm, C
Fuchss, T
Amendt, C
Vassilev, LT
Blaukat, A
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Research team
Cancer Pharmacology & Stress Response (CPSR)
Language
eng
Date accepted
2020-03-11
License start date
2020-05
Citation
Molecular cancer therapeutics, 2020, 19 (5), pp. 1091 - 1101
Publisher
AMER ASSOC CANCER RESEARCH