In:
Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 17, No. 12 ( 2019-12-01), p. 2457-2468
Abstract:
Inhibition of DNA double-strand break (DSB) repair in cancer cells has been proposed as a new therapeutic strategy for potentiating the anticancer effects of radiotherapy. M3814 is a novel, selective pharmacologic inhibitor of the serine/threonine kinase DNA-dependent protein kinase (DNA-PK), a key driver of nonhomologous end-joining, one of the main DSB-repair pathways, currently under clinical investigation. Here, we show that M3814 effectively blocks the repair of radiation-induced DSBs and potently enhances p53 phosphorylation and activation. In p53 wild-type cells, ataxia telangiectasia–mutated (ATM) and its targets, p53 and checkpoint kinase 2 (CHK2), were more strongly activated by combination treatment with M3814 and radiation than by radiation alone, leading to a complete p53-dependent cell-cycle block and premature cell senescence. Cancer cells with dysfunctional p53 were unable to fully arrest their cell cycle and entered S and M phases with unrepaired DNA, leading to mitotic catastrophe and apoptotic cell death. Isogenic p53-null/wild-type A549 and HT-1080 cell lines were generated and used to demonstrate that p53 plays a critical role in determining the response to ionizing radiation and M3814. Time-lapse imaging of cell death and measuring apoptosis in panels of p53 wild-type and p53-null/mutant cancer lines confirmed the clear differences in cell fate, dependent on p53 status. Implications: Our results identify p53 as a possible biomarker for response of cancer cells to combination treatment with radiation and a DNA-PK inhibitor and suggest that p53 mutation status should be considered in the design of future clinical trials. Visual Overview: http://mcr.aacrjournals.org/content/molcanres/17/12/2457/F1.large.jpg.
Type of Medium:
Online Resource
ISSN:
1541-7786
,
1557-3125
DOI:
10.1158/1541-7786.MCR-19-0362
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2019
detail.hit.zdb_id:
2097884-4
SSG:
12
