Pre-clinical activity of the oral DNA-PK inhibitor, peposertib (M3814), combined with radiation in xenograft models of cervical cancer Journal Article

   

Authors:	Gordhandas, S. B.; Manning-Geist, B.; Henson, C.; Iyer, G.; Gardner, G. J.; Sonoda, Y.; Moore, K. N.; Aghajanian, C.; Chui, M. H.; Grisham, R. N.
Article Title:	Pre-clinical activity of the oral DNA-PK inhibitor, peposertib (M3814), combined with radiation in xenograft models of cervical cancer
Abstract:	DNA-dependent protein kinase (DNA-PK) plays a crucial role in repair of DNA double-strand breaks by facilitating non-homologous end-joining. Inhibitors of DNA-PK have the potential to block DNA repair and enhance DNA-damaging agents. Peposertib (M3814) is a DNA-PK inhibitor that has shown preclinical activity in combination with DNA-damaging agents, including ionizing radiation (IR) and topoisomerase II inhibitors. Here we evaluated the activity of peposertib (M3814) in combination with radiation in a mouse xenograft model of HPV-associated cervical cancer. Athymic nude female mice with established tumors derived from HeLa cells injected into the flank were treated with vehicle alone (n = 3), IR alone (n = 4), and peposertib (M38814) in combination with IR (M3814 + IR; n = 4). While IR alone was associated with a trend towards decreased tumor volume compared with untreated, only the M3814 + IR treatment arm was associated with consistent and significant reduction in tumor burden, which correlated with higher levels of γ-H2AX in tumor cells, a marker of double-strand DNA breaks. Our data support further clinical evaluation of the combination of peposertib (M38814) and IR in cervical cancer. © 2022, The Author(s).
Journal Title:	Scientific Reports
Volume:	12
ISSN:	2045-2322
Publisher:	Nature Publishing Group
Date Published:	2022-01-19
Start Page:	974
Language:	English
DOI:	10.1038/s41598-021-04618-5
PROVIDER:	scopus
PMCID:	PMC8770623
PUBMED:	35046420
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85123088629&doi=10.1038%2fs41598-021-04618-5&partnerID=40&md5=87316c462294d592e46d8ec1f032b33b
Notes:	Article -- Export Date: 1 February 2022 -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/192240