Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes

Al-Ejeh, F., Kumar, R., Wiegmans, A., Lakhani, S.R., Brown, M.P. and Khanna, K.K. (2010) Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes. Oncogene, 29 46: 6085-6098. doi:10.1038/onc.2010.407

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Author Al-Ejeh, F.
Kumar, R.
Wiegmans, A.
Lakhani, S.R.
Brown, M.P.
Khanna, K.K.
Title Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes
Journal name Oncogene   Check publisher's open access policy
ISSN 0950-9232
Publication date 2010-11-18
Sub-type Article (original research)
DOI 10.1038/onc.2010.407
Volume 29
Issue 46
Start page 6085
End page 6098
Total pages 14
Place of publication United Kingdom
Publisher Nature Publishing Group
Collection year 2011
Language eng
Abstract The DNA-damage response (DDR) pathways consist of interconnected components that respond to DNA damage to allow repair and promote cell survival. The DNA repair pathways and downstream cellular responses have diverged in cancer cells compared with normal cells because of genetic alterations that underlie drug resistance, disabled repair and resistance to apoptosis. Consequently, abrogating DDR pathways represents an important mechanism for enhancing the therapeutic index of DNA-damaging anticancer agents. In this review, we discuss the DDR pathways that determine antitumor effects of DNA-damaging agents with a specific focus on treatment outcomes in tumors carrying a defective p53 pathway. Finely tuned survival and death pathways govern the cellular responses downstream of the cytotoxic insults inherent in anticancer treatment. The significance and relative contributions of cellular responses including apoptosis, mitotic catastrophe and senescence are discussed in relation to the web of molecular interactions that affect such outcomes. We propose that promising combinations of DNA-damaging anticancer treatments with DDR-pathway inhibition would be further enhanced by activating downstream apoptotic pathways. The proposed rationale ensures that actual cell death is the preferred outcome of cancer treatment instead of other responses, including reversible cell cycle arrest, autophagy or senescence. Finally, to better measure the contribution of different cellular responses to anticancer treatments, multiplex in vivo assessments of therapy-induced response pathways such as cell death, senescence and mitotic catastrophe is desirable rather than the current reliance on the measurement of a single response pathway such as apoptosis. © 2010 Macmillan Publishers Limited All rights reserved.
Keyword Cell cycle checkpoints
Cell death
Cellular senescence
DNA repair
DNA-damage response
Mitotic catastrophe
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2011 Collection
School of Medicine Publications
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Created: Fri, 01 Apr 2011, 08:42:19 EST by Debbie Banks on behalf of School of Medicine