Archives

  • 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04

    • It has also been reported that defects

    2023-02-01

    It has also been reported that defects in ATM or ATR signalling are synthetically lethal with PARP inhibition (Turner et al., 2008, Peasland et al., 2011, Yap et al., 2011, Michels et al., 2014), suggesting that combined inhibition of PARP and ATM or ATR may be an effective therapeutic strategy. In addition to intrinsic defects in DDR, tumour ceftiofur may also acquire conditional DDR defects. Under hypoxic conditions, the expression of several proteins involved in homologous recombination is down-regulated, conferring sensitivity to ATR inhibition (Chan et al., 2010, Pires et al., 2012). Potentially, patient subgroups with high levels of tumour hypoxia could be identified by immunohistochemistry (Loncaster et al., 2001), using gene expression arrays (Eustace et al., 2013), or by non-invasive imaging (e.g. with 18F-Misonidazole PET (Eschmann et al., 2005)). In the early stages of clinical development, it is crucial to demonstrate that a new drug inhibits its target sufficiently to modulate relevant pathways to elicit a biological response. For ATM inhibitors, a number of potential measures of target inhibition have been identified, including ATM autophosphorylation, or phosphorylation of the ATM downstream targets p53, KAP1, SMC1, CHK2, and H2AX (γH2AX) (Shiloh and Ziv, 2013, Guo et al., 2014). A caveat is that several of these markers, including p53 and γH2AX are not specific measures of ATM kinase activity as they may also be targets of other kinases, including DNA-PKcs and ATR (Hammond et al., 2003, Mukherjee et al., 2006). The use of a panel of these markers is likely to be most informative in evaluating the activity of ATM inhibitors in the clinic (Bartkova et al., 2005, Kozlov et al., 2011). CHK1 phosphorylation is the most widely used preclinical biomarker of ATR kinase activity (Fokas et al., 2012, Pires et al., 2012, Hall et al., 2014). However, ATM can also phosphorylate CHK1 (Gatei et al., 2003, Sørensen et al., 2003, Helt et al., 2005), albeit to a lesser extent and a recent study in ovarian cancer has suggested that CHK1 phosphorylation status may not offer a reliable marker for inhibition of the ATR-CHK1 pathway (Huntoon et al., 2013). Other, less direct, measures of ATR inhibitor activity could include increased DNA replication stress markers such as pan-nuclear γH2AX (Jacq et al., 2012, Foote et al., 2013, Guichard et al., 2013, Jones et al., 2013) or nuclear foci staining of RPA or RAD51, a marker for homologous recombination repair, but these are unlikely to be specific pathway markers of ATR inhibition. Finally, the biological consequence of ATM/ATR target and pathway inhibition, either in combination with genotoxic therapy, or as a synthetic lethal monotherapy in DDR-defective tumours is selective tumour cell death which would be expected to produce tumour shrinkage in the clinical setting measurable by standard RECIST criteria (Fojo & Noonan, 2012) with the potential for assessing early circulating markers of apoptosis (Ward et al., 2008).
    Conclusion
    Conflict of interest
    Acknowledgments This work was supported by grants from the Medical Research Council (UK) (A.J.R.) (MC_PC_12006) and Cancer Research UK (A.M.W.) (18443) The funding bodies had no involvement in the writing of this review or in the decision to submit for publication.
    Main Text
    Acknowledgments We apologize to all colleagues whose important findings could not be cited owing to space limitations. We are grateful to Tom Blundell for permission to reproduce the crystal structure of DNA-PKcs. We thank Gabriel Balmus, Kate Dry, Josep Forment, Donna Lowe, Wojciech Niedzwiedz, Christine Schmidt, and Paul Wijnhoven for critical reading of the manuscript. A.N.B. is supported by a Cancer Research UK (CRUK) Career Development Fellowship (C29215/A20772). Research in the S.P.J. laboratory is funded by CRUK program grant C6/A18796 and a Wellcome Trust Investigator Award (206388/Z/17/Z), with core institute support from CRUK (C6946/A14492) and the Wellcome Trust (WT092096). S.P.J. receives his salary from the University of Cambridge, UK, supplemented by CRUK (C4750/A21839).