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Lookup NU author(s): Dr Elaine WillmoreORCiD, Dr sarah Johnson, Dr Tryfonia Mainou-Fowler, Professor Graham Jackson, Dr Celine CanoORCiD, Professor Roger Griffin, Dr Ian CowellORCiD, Professor Caroline AustinORCiD, Professor barbara Durkacz
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Purpose: del(17p), del(11q), and associated p53 dysfunction predict for short survival and chemoresistance in B-cell chronic lymphocytic leukemia (CLL). DNA-dependent protein kinase (DNA-PK) is activated by DNA damage and mediates DNA double-strand break repair. We hypothesized that inhibiting DNA-PK would sensitize CLL cells to drug-induced DNA damage and that this approach could increase the therapeutic index of agents used to treat CLL. Experimental Design: Fifty-four CLL cases were characterized for poor prognosis markers [del(17p), del(11q), CD38, and ZAP-70]. In selected cases, DNA-PK catalytic subunit (DNA-PKcs) expression and activity and p53 function were also measured. Ex vivo viability assays established sensitivity to fludarabine and chlorambucil and also tested the ability of a novel DNA-PK inhibitor (NU7441) to sensitize CLL cells to these drugs. The effects of NU7441 on fludarabine-induced DNA damage repair were also assessed (Comet assays and detection of γH2AX). Results: DNA-PKcs levels correlated with DNA-PK activity and varied 50-fold between cases but were consistently higher in del(17p) (P = 0.01) and del(11q) cases. NU7441 sensitized CLL cells to chlorambucil and fludarabine, including cases with del(17p), del(11q), p53 dysfunction, or high levels of DNA-PKcs. NU7441 increased fludarabine-induced double-strand breaks and abrogated drug-induced autophosphorylation of DNA-PKcs at Ser2056. High DNA-PK levels predicted for reduced treatment-free interval. Conclusions: These data validate the concept of targeting DNA-PKcs in poor risk CLL, and demonstrate a mechanistic rationale for use of a DNA-PK inhibitor. The novel observation that DNA-PKcs is overexpressed in del(17p) and del(11q) cases indicates that DNA-PK may contribute to disease progression in CLL.
Author(s): Willmore E, Elliott SL, Mainou-Fowler T, Summerfield GP, Jackson GH, O'Neill F, Lowe C, Carter A, Harris R, Pettitt AR, Cano-Soumillac C, Griffin RJ, Cowell IG, Austin CA, Durkacz BW
Publication type: Article
Publication status: Published
Journal: Clinical Cancer Research
Year: 2008
Volume: 14
Issue: 12
Pages: 3984-3992
ISSN (print): 1078-0432
ISSN (electronic): 1557-3265
Publisher: American Association for Cancer Research
URL: http://dx.doi.org/10.1158/1078-0432.CCR-07-5158
DOI: 10.1158/1078-0432.CCR-07-5158
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