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The potential of exploiting DNA-repair defects for optimizing lung cancer treatment

Nature Reviews Clinical Oncology volume 9, pages 144–155 (2012)Cite this article

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Abstract

The tumor genome is commonly aberrant as a consequence of mutagenic insult and incomplete DNA repair. DNA repair as a therapeutic target has recently received considerable attention owing to the promise of drugs that target tumor-specific DNA-repair enzymes and potentiate conventional cytotoxic therapy through mechanism-based approaches, such as synthetic lethality. Treatment for non-small-cell lung cancer (NSCLC) consists mainly of platinum-based chemotherapy regimens and improvements are urgently needed. Optimizing treatment according to tumor status for DNA-repair biomarkers, such as ERCC1, BRCA1 or RRM1, could predict response to platinum, taxanes and gemcitabine-based therapies, respectively, and might improve substantially the response of individual patients' tumors. Finally, recent data on germline variation in DNA-repair genes may also be informative. Here, we discuss how a molecular and functional DNA-repair classification of NSCLC may aid clinical decision making and improve patient outcome.

Key Points

  • Non-small-cell lung cancer (NSCLC) is the leading cause of cancer death worldwide and displays frequent DNA repair dysfunctionality

  • Targeting DNA repair can be a therapeutic strategy in itself, notably using mechanism-based approaches, such as synthetic lethality, chemosensitazion or radiosensitization

  • Several DNA-repair biomarkers, such as ERCC1, BRCA1, RAP80, RRM1, PARP1, MSH2 or DNA-PK, could be used to customize NSCLC therapy and substantially improve patient outcomes

  • Functional DNA-repair assays should be implemented in addition to biomarker analysis to select patients that could benefit from mechanism-based treatments

  • Besides tumor characteristics, host DNA-repair gene profiles could provide useful information

  • Current challenges include the prospective validation of such biomarkers, the choice of methods to analyze such biomarkers molecularly and functionally, and the implementation of the results in clinical decision making

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Figure 1: Main DNA lesions and corresponding DNA-damage-repair pathways.
Figure 2: DNA repair as a therapeutic target.
Figure 3: DNA-repair biomarkers and therapeutic implication.

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Acknowledgements

We thank Cédric Verjat for his contribution to the graphical design of the figures. S. Postel-Vinay's PhD is funded by an ESMO translational research fellowship as well as an Institut National du Cancer fellowship 'Soutien pour la formation à la recherche translationnelle en cancérologie 2011'.

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  1. Department of Medicine, INSERM U981, Université Paris-Sud XI–Institut Gustave Roussy, 114 rue Edouard Vaillant, Villejuif, 94805, France

    Sophie Postel-Vinay, Elsa Vanhecke, Ken A. Olaussen & Jean-Charles Soria

  2. The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, Fulham Road, London, SW3 6JB, UK

    Christopher J. Lord & Alan Ashworth

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S. Postel-Vinay researched the data for the article. All authors made a substantial contribution to the discussion of the content, wrote the article and edited it prior to submission.

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J.-C. Soria declares he is a consultant for AstraZeneca, Merck and Sanofi-Aventis and owner of patent WO 2007/105110. C. Lord and A. Ashworth are owners of patents describing the use of PARP inhibitors and also stand to benefit from the ICR 'Rewards to inventors scheme'. The other authors declare no competing interests.

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Postel-Vinay, S., Vanhecke, E., Olaussen, K. et al. The potential of exploiting DNA-repair defects for optimizing lung cancer treatment. Nat Rev Clin Oncol 9, 144–155 (2012). https://doi.org/10.1038/nrclinonc.2012.3

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