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PARP Inhibitor Resistance—What Is Beyond BRCA1 or BRCA2 Restoration?

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PARP Inhibitors for Cancer Therapy

Part of the book series: Cancer Drug Discovery and Development ((CDD&D,volume 83))

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Abstract

Nearly 10 years ago the usefulness of poly(ADP-ribose) polymerase (PARP) inhibitors to kill BRCA1 or BRCA2-deficient cells was reported, and this finding has served as a prime example of the concept of synthetic lethality in the context of anticancer therapy. The clinical translation of this finding has undergone several ups and downs, however. Despite spectacular responses seen in some patients with BRCA-deficient breast or ovarian cancers, other patients did not show the expected benefit from PARP inhibitor therapy. Thus, like for all novel tailored anti-cancer drugs, upfront and secondary resistance remain major hurdles in the implementation of the initial preclinical finding. We know at least one clinically relevant mechanism of PARP inhibitor resistance: the reversion of BRCA function by secondary mutations. Nevertheless, it is also clear that this mechanism does not explain all cases of resistance. At the moment, we only have a poor understanding of BRCA reversion-independent resistance mechanisms. Preclinical data have pointed in several directions, e.g. increased drug efflux, reduced drug target levels, or alternative DNA repair. Here, we discuss these mechanisms with a focus on potential DNA repair adaptations.

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Acknowledgements

We wish to thank Piet Borst, Peter Bouwman and Ewa Gogola for critical reading of the manuscript. Nora Gerhards helped with the design of Fig. 19.1. Our work on PARPi resistance is supported by grants from the Netherlands Organization for Scientific Research (NWO-VIDI-91711302 to S. Rottenberg; NWO-VICI 91814643 to J. Jonkers), and the Dutch Cancer Society (KWF projects NKI 2009-4303, NKI 2011-5197 and NKI 2011-5220), and the Swiss National Science Foundation (310030_156869).

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  1. Division of Molecular Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands

    Guotai Xu, Jos Jonkers & Sven Rottenberg

  2. Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Länggassstr. 122, 3012, Bern, Switzerland

    Sven Rottenberg

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  1. Guotai Xu
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Correspondence to Sven Rottenberg .

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  1. Northern Institute for Cancer Research and Newcastle University Institute for Ageing Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom

    Nicola J. Curtin

  2. CRUK-MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom

    Ricky A. Sharma

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Xu, G., Jonkers, J., Rottenberg, S. (2015). PARP Inhibitor Resistance—What Is Beyond BRCA1 or BRCA2 Restoration?. In: Curtin, N., Sharma, R. (eds) PARP Inhibitors for Cancer Therapy. Cancer Drug Discovery and Development, vol 83. Humana Press, Cham. https://doi.org/10.1007/978-3-319-14151-0_19

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