A cell-based screen identifies ATR inhibitors with synthetic lethal properties for cancer-associated mutations (original) (raw)

• Lempiäinen, H. & Halazonetis, T.D. Emerging common themes in regulation of PIKKs and PI3Ks. EMBO J. 28, 3067–3073 (2009).
  Article PubMed PubMed Central Google Scholar
• López-Contreras, A.J. & Fernandez-Capetillo, O. The ATR barrier to replication-born DNA damage. DNA Repair (Amst.) 9, 1249–1255 (2010).
  Article Google Scholar
• Bartkova, J. et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434, 864–870 (2005).
  Article CAS PubMed Google Scholar
• Gorgoulis, V.G. et al. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434, 907–913 (2005).
  Article CAS PubMed Google Scholar
• Halazonetis, T.D., Gorgoulis, V.G. & Bartek, J. An oncogene-induced DNA damage model for cancer development. Science 319, 1352–1355 (2008).
  Article CAS PubMed Google Scholar
• Bartkova, J. et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444, 633–637 (2006).
  Article CAS PubMed Google Scholar
• Di Micco, R. et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444, 638–642 (2006).
  Article CAS PubMed Google Scholar
• Mallette, F.A., Gaumont-Leclerc, M.F. & Ferbeyre, G. The DNA damage signaling pathway is a critical mediator of oncogene-induced senescence. Genes Dev. 21, 43–48 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Cimprich, K.A. & Cortez, D. ATR: an essential regulator of genome integrity. Nat. Rev. Mol. Cell Biol. 9, 616–627 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Toledo, L.I., Murga, M., Gutierrez-Martinez, P., Soria, R. & Fernandez-Capetillo, O. ATR signaling can drive cells into senescence in the absence of DNA breaks. Genes Dev. 22, 297–302 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Kumagai, A., Lee, J., Yoo, H.Y. & Dunphy, W.G. TopBP1 activates the ATR-ATRIP complex. Cell 124, 943–955 (2006).
  Article CAS PubMed Google Scholar
• Link, W. et al. Chemical interrogation of FOXO3a nuclear translocation identifies potent and selective inhibitors of phosphoinositide 3-kinases. J. Biol. Chem. 284, 28392–28400 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Cliby, W.A. et al. Overexpression of a kinase-inactive ATR protein causes sensitivity to DNA-damaging agents and defects in cell cycle checkpoints. EMBO J. 17, 159–169 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Bakkenist, C.J. & Kastan, M.B. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421, 499–506 (2003).
  Article CAS PubMed Google Scholar
• Cuadrado, M. et al. ATM regulates ATR chromatin loading in response to DNA double-strand breaks. J. Exp. Med. 203, 297–303 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Jazayeri, A. et al. ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks. Nat. Cell Biol. 8, 37–45 (2006).
  Article CAS PubMed Google Scholar
• Matsuoka, S., Huang, M. & Elledge, S.J. Linkage of ATM to cell cycle regulation by the Chk2 protein kinase. Science 282, 1893–1897 (1998).
  Article CAS PubMed Google Scholar
• Chen, B.P. et al. Cell cycle dependence of DNA-dependent protein kinase phosphorylation in response to DNA double strand breaks. J. Biol. Chem. 280, 14709–14715 (2005).
  Article CAS PubMed Google Scholar
• Stiff, T. et al. ATM and DNA-PK function redundantly to phosphorylate H2AX after exposure to ionizing radiation. Cancer Res. 64, 2390–2396 (2004).
  Article CAS PubMed Google Scholar
• Maira, S.M. et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol. Cancer Ther. 7, 1851–1863 (2008).
  Article CAS PubMed Google Scholar
• García-Echeverría, C. et al. In vivo antitumor activity of NVP-AEW541—a novel, potent, and selective inhibitor of the IGF-IR kinase. Cancer Cell 5, 231–239 (2004).
  Article PubMed Google Scholar
• Petermann, E., Orta, M.L., Issaeva, N., Schultz, N. & Helleday, T. Hydroxyurea-stalled replication forks become progressively inactivated and require two different RAD51-mediated pathways for restart and repair. Mol. Cell 37, 492–502 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Murga, M. et al. A mouse model of ATR-Seckel shows embryonic DNA replicative stress and accelerated ageing. Nat. Genet. 8, 891–898 (2009).
  Article Google Scholar
• Barlow, C. et al. Atm-deficient mice: a paradigm of ataxia telangiectasia. Cell 86, 159–171 (1996).
  Article CAS PubMed Google Scholar
• Elson, A. et al. Pleiotropic defects in ataxia-telangiectasia protein-deficient mice. Proc. Natl. Acad. Sci. USA 93, 13084–13089 (1996).
  Article CAS PubMed PubMed Central Google Scholar
• Xu, Y. & Baltimore, D. Dual roles of ATM in the cellular response to radiation and in cell growth control. Genes Dev. 10, 2401–2410 (1996).
  Article CAS PubMed Google Scholar
• Taccioli, G.E. et al. Targeted disruption of the catalytic subunit of the DNA-PK gene in mice confers severe combined immunodeficiency and radiosensitivity. Immunity 9, 355–366 (1998).
  Article CAS PubMed Google Scholar
• Brown, E.J. & Baltimore, D. ATR disruption leads to chromosomal fragmentation and early embryonic lethality. Genes Dev. 14, 397–402 (2000).
  CAS PubMed PubMed Central Google Scholar
• de Klein, A. et al. Targeted disruption of the cell-cycle checkpoint gene ATR leads to early embryonic lethality in mice. Curr. Biol. 10, 479–482 (2000).
  Article CAS PubMed Google Scholar
• Liu, Q. et al. Chk1 is an essential kinase that is regulated by Atr and required for the G2/M DNA damage checkpoint. Genes Dev. 14, 1448–1459 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Takai, H. et al. Aberrant cell cycle checkpoint function and early embryonic death in Chk1 −/− mice. Genes Dev. 14, 1439–1447 (2000).
  CAS PubMed PubMed Central Google Scholar
• Syljuåsen, R.G. et al. Inhibition of human Chk1 causes increased initiation of DNA replication, phosphorylation of ATR targets, and DNA breakage. Mol. Cell. Biol. 25, 3553–3562 (2005).
  Article PubMed PubMed Central Google Scholar
• Beck, H. et al. Regulators of cyclin-dependent kinases are crucial for maintaining genome integrity in S phase. J. Cell Biol. 188, 629–638 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Ruzankina, Y. et al. Tissue regenerative delays and synthetic lethality in adult mice after combined deletion of Atr and Trp53. Nat. Genet. 41, 1144–1149 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Koniaras, K., Cuddihy, A.R., Christopoulos, H., Hogg, A. & O'Connell, M.J. Inhibition of Chk1-dependent G2 DNA damage checkpoint radiosensitizes p53 mutant human cells. Oncogene 20, 7453–7463 (2001).
  Article CAS PubMed Google Scholar
• Ekholm-Reed, S. et al. Deregulation of cyclin E in human cells interferes with prereplication complex assembly. J. Cell Biol. 165, 789–800 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Spruck, C.H., Won, K.A. & Reed, S.I. Deregulated cyclin E induces chromosome instability. Nature 401, 297–300 (1999).
  Article CAS PubMed Google Scholar
• Myers, K., Gagou, M.E., Zuazua-Villar, P., Rodriguez, R. & Meuth, M. ATR and Chk1 suppress a caspase-3-dependent apoptotic response following DNA replication stress. PLoS Genet. 5, e1000324 (2009).
  Article PubMed PubMed Central Google Scholar
• Sidi, S. et al. Chk1 suppresses a caspase-2 apoptotic response to DNA damage that bypasses p53, Bcl-2, and caspase-3. Cell 133, 864–877 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Hickson, I. et al. Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM. Cancer Res. 64, 9152–9159 (2004).
  Article CAS PubMed Google Scholar
• Willmore, E. et al. A novel DNA-dependent protein kinase inhibitor, NU7026, potentiates the cytotoxicity of topoisomerase II poisons used in the treatment of leukemia. Blood 103, 4659–4665 (2004).
  Article CAS PubMed Google Scholar
• Nishida, H. et al. Inhibition of ATR protein kinase activity by schisandrin B in DNA damage response. Nucleic Acids Res. 37, 5678–5689 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Konstantinidou, G. et al. Dual phosphoinositide 3-kinase/mammalian target of rapamycin blockade is an effective radiosensitizing strategy for the treatment of non-small cell lung cancer harboring K-RAS mutations. Cancer Res. 69, 7644–7652 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Gilad, O. et al. Combining ATR suppression with oncogenic Ras synergistically increases genomic instability, causing synthetic lethality or tumorigenesis in a dosage-dependent manner. Cancer Res. 70, 9693–9702 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Bartek, J., Bartkova, J. & Lukas, J. DNA damage signalling guards against activated oncogenes and tumour progression. Oncogene 26, 7773–7779 (2007).
  Article CAS PubMed Google Scholar
• Bryant, H.E. et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913–917 (2005).
  Article CAS PubMed Google Scholar
• Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005).
  Article CAS PubMed Google Scholar
• Negrini, S., Gorgoulis, V.G. & Halazonetis, T.D. Genomic instability—an evolving hallmark of cancer. Nat. Rev. Mol. Cell Biol. 11, 220–228 (2010).
  Article CAS PubMed Google Scholar
• Donehower, L.A. et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356, 215–221 (1992).
  Article CAS PubMed Google Scholar
• Silva, J.M. et al. Second-generation shRNA libraries covering the mouse and human genomes. Nat. Genet. 37, 1281–1288 (2005).
  Article CAS PubMed Google Scholar