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

Oncogene volume 29, pages 6085–6098 (2010)Cite this article

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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.

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Acknowledgements

This work was supported by the Cancer Council NSW (IG 09-04 to FA); The Cure Cancer Foundation Australia (ID 631924 to FA); the Cancer Council SA (ID 631923 to FA); National Health & Medical Research Council Program Grant (ID 442903 to SRL and KKK); and Australian Research Council Grant (ID DP0880372 to KKK)

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Authors and Affiliations

  1. Signal Transduction Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland, Australia

    F Al-Ejeh, A Wiegmans & K K Khanna

  2. Breast Cancer Genetics Group, Discipline of Medicine, University of Adelaide and Hanson Institute, SA Pathology, Adelaide, South Australia, Australia,

    R Kumar

  3. School of Medicine and Pathology Queensland, The Royal Brisbane & Women's Hospital,

    S R Lakhani

  4. University of Queensland Centre for Clinical Research (UQCCR), Brisbane, Queensland, Australia

    S R Lakhani

  5. Cancer Clinical Trials Unit, Royal Adelaide Hospital Cancer Centre, Adelaide, South Australia, Australia,

    M P Brown

  6. School of Medicine, University of Adelaide, Adelaide, South Australia, Australia,

    M P Brown

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  1. F Al-Ejeh
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Al-Ejeh, F., Kumar, R., Wiegmans, A. et al. Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes. Oncogene 29, 6085–6098 (2010). https://doi.org/10.1038/onc.2010.407

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