ATR inhibitors VE-821 and VX-970 sensitize cancer cells to topoisomerase I inhibitors by disabling DNA replication initiation and fork elongation responses. Josse, R., S.E., M., Guha, R., Ormanoglu, P., Pfister, T., Morris, J., Doroshow, J., & Pommier, Y. Cancer. Res., 74(23):6968--6979, 2014. abstract bibtex Camptothecin, a specific topoisomerase I inhibitor is a potent anticancer drug, especially against solid tumors. This agent produces well-characterized double-strand breaks upon collision of replication forks with topoisomerase I cleavage complexes. In an attempt to improve its efficacy, we conducted a synthetic lethal siRNA screening using a library that targets nearly 7000 human genes. Depletion of ATR, the main transducer of replication stress-induced DNA damage response exacerbated cytotoxic response to both camptothecin and the indenoisoquinoline LMP-400, a novel class of topoisomerase inhibitors in clinical trial. Inhibition of ATR by the recently developed specific inhibitor VE-821 induced synergistic antiproliferative activity when combined with either topoisomerase inhibitor. Cytotoxicity induced by the combination with LMP-400 was greater than with camptothecin. Using single cell analysis and DNA fiber spread, we show that VE-821 abrogated the S-phase checkpoint, restored origin firing and replication fork progression. Moreover, the combination of a topoisomerase inhibitor with VE-821 inhibited the phosphorylation of ATR and ATR-mediated Chk1 phosphorylation but strongly induced γH2AX. Single cell analysis revealed that γH2AX pattern changed overtime from well-defined focus to a pan-nuclear staining. The change in γH2AX pattern can be useful as a predictive biomarker to evaluate the efficacy of therapy. The key implication of our work is the clinical rationale it provides to evaluate the combination of indenoisoquinoline topoisomerase I inhibitors with ATR inhibitors.
@article{Josse:2014yu,
Abstract = {Camptothecin, a specific topoisomerase I inhibitor is a potent anticancer drug, especially against solid tumors. This agent produces well-characterized double-strand breaks upon collision of replication forks with topoisomerase I cleavage complexes. In an attempt to improve its efficacy, we conducted a synthetic lethal siRNA screening using a library that targets nearly 7000 human genes. Depletion of ATR, the main transducer of replication stress-induced DNA damage response exacerbated cytotoxic response to both camptothecin and the indenoisoquinoline LMP-400, a novel class of topoisomerase inhibitors in clinical trial. Inhibition of ATR by the recently developed specific inhibitor VE-821 induced synergistic antiproliferative activity when combined with either topoisomerase inhibitor. Cytotoxicity induced by the combination with LMP-400 was greater than with camptothecin. Using single cell analysis and DNA fiber spread, we show that VE-821 abrogated the S-phase checkpoint, restored origin firing and replication fork progression. Moreover, the combination of a topoisomerase inhibitor with VE-821 inhibited the phosphorylation of ATR and ATR-mediated Chk1 phosphorylation but strongly induced γH2AX. Single cell analysis revealed that γH2AX pattern changed overtime from well-defined focus to a pan-nuclear staining. The change in γH2AX pattern can be useful as a predictive biomarker to evaluate the efficacy of therapy. The key implication of our work is the clinical rationale it provides to evaluate the combination of indenoisoquinoline topoisomerase I inhibitors with ATR inhibitors.},
Author = {Josse, R. and Martin S.E. and Guha, R. and Ormanoglu, P. and Pfister, T. and Morris, J. and Doroshow, J. and Pommier, Y.},
Date-Added = {2013-11-26 14:02:37 +0000},
Date-Modified = {2015-01-22 16:22:36 +0000},
Journal = {Cancer. Res.},
Keywords = {cancer; atr; sirna; rnai; hts},
Number = {23},
Pages = {6968--6979},
Title = {{ATR} inhibitors {VE-821} and {VX-970} sensitize cancer cells to topoisomerase {I} inhibitors by disabling {DNA} replication initiation and fork elongation responses},
Volume = {74},
Year = {2014},
Bdsk-Url-1 = {http://dx.doi.org/10.1158/0008-5472.CAN-13-3369}}
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