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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics

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Models and Technologies

Modeling Therapy Resistance in BRCA1/2-Mutant Cancers

Amy Dréan, Chris T. Williamson, Rachel Brough, Inger Brandsma, Malini Menon, Asha Konde, Isaac Garcia-Murillas, Helen N. Pemberton, Jessica Frankum, Rumana Rafiq, Nicholas Badham, James Campbell, Aditi Gulati, Nicholas C. Turner, Stephen J. Pettitt, Alan Ashworth and Christopher J. Lord
Amy Dréan
The CRUK Gene Function Laboratory and The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
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Chris T. Williamson
The CRUK Gene Function Laboratory and The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
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Rachel Brough
The CRUK Gene Function Laboratory and The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
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Inger Brandsma
The CRUK Gene Function Laboratory and The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
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Malini Menon
The CRUK Gene Function Laboratory and The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
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Asha Konde
The CRUK Gene Function Laboratory and The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
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Isaac Garcia-Murillas
Molecular Oncology Laboratory, The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
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Helen N. Pemberton
The CRUK Gene Function Laboratory and The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
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Jessica Frankum
The CRUK Gene Function Laboratory and The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
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Rumana Rafiq
The CRUK Gene Function Laboratory and The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
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Nicholas Badham
The CRUK Gene Function Laboratory and The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
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James Campbell
The CRUK Gene Function Laboratory and The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
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Aditi Gulati
The CRUK Gene Function Laboratory and The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
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Nicholas C. Turner
Molecular Oncology Laboratory, The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
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Stephen J. Pettitt
The CRUK Gene Function Laboratory and The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
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Alan Ashworth
The CRUK Gene Function Laboratory and The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
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  • For correspondence: Chris.Lord@icr.ac.uk Alan.Ashworth@ucsf.edu
Christopher J. Lord
The CRUK Gene Function Laboratory and The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
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  • For correspondence: Chris.Lord@icr.ac.uk Alan.Ashworth@ucsf.edu
DOI: 10.1158/1535-7163.MCT-17-0098
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Abstract

Although PARP inhibitors target BRCA1- or BRCA2-mutant tumor cells, drug resistance is a problem. PARP inhibitor resistance is sometimes associated with the presence of secondary or “revertant” mutations in BRCA1 or BRCA2. Whether secondary mutant tumor cells are selected for in a Darwinian fashion by treatment is unclear. Furthermore, how PARP inhibitor resistance might be therapeutically targeted is also poorly understood. Using CRISPR mutagenesis, we generated isogenic tumor cell models with secondary BRCA1 or BRCA2 mutations. Using these in heterogeneous in vitro culture or in vivo xenograft experiments in which the clonal composition of tumor cell populations in response to therapy was monitored, we established that PARP inhibitor or platinum salt exposure selects for secondary mutant clones in a Darwinian fashion, with the periodicity of PARP inhibitor administration and the pretreatment frequency of secondary mutant tumor cells influencing the eventual clonal composition of the tumor cell population. In xenograft studies, the presence of secondary mutant cells in tumors impaired the therapeutic effect of a clinical PARP inhibitor. However, we found that both PARP inhibitor–sensitive and PARP inhibitor–resistant BRCA2 mutant tumor cells were sensitive to AZD-1775, a WEE1 kinase inhibitor. In mice carrying heterogeneous tumors, AZD-1775 delivered a greater therapeutic benefit than olaparib treatment. This suggests that despite the restoration of some BRCA1 or BRCA2 gene function in “revertant” tumor cells, vulnerabilities still exist that could be therapeutically exploited. Mol Cancer Ther; 16(9); 1–13. ©2017 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Received January 30, 2017.
  • Revision received May 2, 2017.
  • Accepted June 5, 2017.
  • ©2017 American Association for Cancer Research.
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Published OnlineFirst August 17, 2017
doi: 10.1158/1535-7163.MCT-17-0098

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Modeling Therapy Resistance in BRCA1/2-Mutant Cancers
Amy Dréan, Chris T. Williamson, Rachel Brough, Inger Brandsma, Malini Menon, Asha Konde, Isaac Garcia-Murillas, Helen N. Pemberton, Jessica Frankum, Rumana Rafiq, Nicholas Badham, James Campbell, Aditi Gulati, Nicholas C. Turner, Stephen J. Pettitt, Alan Ashworth and Christopher J. Lord
Mol Cancer Ther August 17 2017 DOI: 10.1158/1535-7163.MCT-17-0098

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Modeling Therapy Resistance in BRCA1/2-Mutant Cancers
Amy Dréan, Chris T. Williamson, Rachel Brough, Inger Brandsma, Malini Menon, Asha Konde, Isaac Garcia-Murillas, Helen N. Pemberton, Jessica Frankum, Rumana Rafiq, Nicholas Badham, James Campbell, Aditi Gulati, Nicholas C. Turner, Stephen J. Pettitt, Alan Ashworth and Christopher J. Lord
Mol Cancer Ther August 17 2017 DOI: 10.1158/1535-7163.MCT-17-0098
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Molecular Cancer Therapeutics
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