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dc.contributor.authorZenke, FT
dc.contributor.authorZimmermann, A
dc.contributor.authorSirrenberg, C
dc.contributor.authorDahmen, H
dc.contributor.authorKirkin, V
dc.contributor.authorPehl, U
dc.contributor.authorGrombacher, T
dc.contributor.authorWilm, C
dc.contributor.authorFuchss, T
dc.contributor.authorAmendt, C
dc.contributor.authorVassilev, LT
dc.contributor.authorBlaukat, A
dc.date.accessioned2020-07-09T10:23:58Z
dc.date.issued2020-05-01
dc.identifier.citationMolecular cancer therapeutics, 2020, 19 (5), pp. 1091 - 1101
dc.identifier.issn1535-7163
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3834
dc.identifier.eissn1538-8514
dc.identifier.doi10.1158/1535-7163.mct-19-0734
dc.description.abstractPhysical 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.formatPrint-Electronic
dc.format.extent1091 - 1101
dc.languageeng
dc.language.isoeng
dc.publisherAMER ASSOC CANCER RESEARCH
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titlePharmacologic Inhibitor of DNA-PK, M3814, Potentiates Radiotherapy and Regresses Human Tumors in Mouse Models.
dc.typeJournal Article
dcterms.dateAccepted2020-03-11
rioxxterms.versionofrecord10.1158/1535-7163.mct-19-0734
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2020-05
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfMolecular cancer therapeutics
pubs.issue5
pubs.notesNot 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-statusPublished
pubs.volume19
pubs.embargo.termsNot known
icr.researchteamCancer Pharmacology & Stress Response (CPSR)
dc.contributor.icrauthorKirkin, Vladimir


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