dc.contributor.author | Zenke, FT | |
dc.contributor.author | Zimmermann, A | |
dc.contributor.author | Sirrenberg, C | |
dc.contributor.author | Dahmen, H | |
dc.contributor.author | Kirkin, V | |
dc.contributor.author | Pehl, U | |
dc.contributor.author | Grombacher, T | |
dc.contributor.author | Wilm, C | |
dc.contributor.author | Fuchss, T | |
dc.contributor.author | Amendt, C | |
dc.contributor.author | Vassilev, LT | |
dc.contributor.author | Blaukat, A | |
dc.date.accessioned | 2020-07-09T10:23:58Z | |
dc.date.issued | 2020-05-01 | |
dc.identifier.citation | Molecular cancer therapeutics, 2020, 19 (5), pp. 1091 - 1101 | |
dc.identifier.issn | 1535-7163 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3834 | |
dc.identifier.eissn | 1538-8514 | |
dc.identifier.doi | 10.1158/1535-7163.mct-19-0734 | |
dc.description.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. | |
dc.format | Print-Electronic | |
dc.format.extent | 1091 - 1101 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER ASSOC CANCER RESEARCH | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.title | Pharmacologic Inhibitor of DNA-PK, M3814, Potentiates Radiotherapy and Regresses Human Tumors in Mouse Models. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2020-03-11 | |
rioxxterms.versionofrecord | 10.1158/1535-7163.mct-19-0734 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2020-05 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Molecular cancer therapeutics | |
pubs.issue | 5 | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Pharmacology & Stress Response (CPSR) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Pharmacology & Stress Response (CPSR) | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Pharmacology & Stress Response (CPSR) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Pharmacology & Stress Response (CPSR) | |
pubs.publication-status | Published | |
pubs.volume | 19 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Cancer Pharmacology & Stress Response (CPSR) | |
dc.contributor.icrauthor | Kirkin, Vladimir | |