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PARP Inhibitors for Cancer Therapy pp 431–452Cite as

Resistance to PARP Inhibitors Mediated by Secondary BRCA1/2 Mutations

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

Abstract

PARP inhibitors are a promising class of chemotherapy agents that have shown efficacy in the treatment of BRCA1/2-deficient tumors. Treatment with these small molecule inhibitors in a homologous recombination repair (HRR) deficient background results in synthetic lethality. However, cancer cells can become resistant to PARP inhibitors by several different mechanisms. A major mechanism of PARP inhibitor resistance is restoration of functional BRCA1/2 by secondary BRCA1/2 mutation. BRCA1/2 restoration cancels synthetic lethality as it leads to functional HRR-mediated DNA repair. Loss of 53BP1 expression in BRCA1-mutated cancer cells can also lead to PARP inhibitor resistance by partial restoration of HRR. Additional mechanisms of PARP inhibitor resistance include increased P-glycoprotein expression that results in increased efflux of the drug and loss of PARP1 expression that prevents formation of toxic DNA-PARP1 lesions. Here, we focus on PARP inhibitor resistance by BRCA1/2 restoration and potential clinical implications of this phenomenon. We also briefly discuss the other known and possible mechanisms of PARP resistance.

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Acknowledgments

We thank all the members of Taniguchi lab for discussion and comments and Drs. Elizabeth Swisher and Ronald Cheung for critical reading of the manuscript. This work was supported by NIH/NCI grants (R01CA125636 to T.T., Pacific Ovarian Cancer Research Consortium (P50 CA083636 to T.T.), and Chromosome Metabolism and Cancer Training Grant (T32CA09657) and Thomsen Family Breast Cancer Postdoctoral Research Fellowship to K.K.D., and Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., C1-015, 98109-1024, Seattle, WA, USA

    Kiranjit K. Dhillon & Toshiyasu Taniguchi

  2. Howard Hughes Medical Institute, Chevy Chase, USA

    Kiranjit K. Dhillon & Toshiyasu Taniguchi

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  1. Kiranjit K. Dhillon
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  2. Toshiyasu Taniguchi
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Correspondence to Toshiyasu Taniguchi .

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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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Dhillon, K., Taniguchi, T. (2015). Resistance to PARP Inhibitors Mediated by Secondary BRCA1/2 Mutations. 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_18

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  • DOI: https://doi.org/10.1007/978-3-319-14151-0_18

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  • Online ISBN: 978-3-319-14151-0

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