Pre-clinical activity of the oral DNA-PK inhibitor, peposertib (M3814), combined with radiation in xenograft models of cervical cancer.
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| 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.
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| Authors | Sushmita B Gordhandas, Beryl Manning-Geist, Christina Henson, Gopa Iyer, Ginger J Gardner, Yukio Sonoda, Kathleen N Moore, Carol Aghajanian, M Herman Chui, Rachel N Grisham |
| Journal | Scientific reports (Sci Rep) Vol. 12 Issue 1 Pg. 974 (01 19 2022) ISSN: 2045-2322 [Electronic] England |
| PMID | 35046420 (Publication Type: Journal Article, Research Support, N.I.H., Extramural) |
| Copyright | © 2022. The Author(s). |
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