The DOI matches its Crossref record; 7 of the 7 references it cites were found in a registry or an index.
High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs
Open accessAbstract
Whereas target-specific drugs are available for treating ERBB2-overexpressing and hormone receptor-positive breast cancers, no tailored therapy exists for hormone receptor- and ERBB2-negative (“triple-negative”) mammary carcinomas. Triple-negative tumors account for 15% of all breast cancers and frequently harbor defects in DNA double-strand break repair through homologous recombination (HR), such as BRCA1 dysfunction. The DNA-repair defects characteristic of BRCA1-deficient cells confer sensitivity to poly(ADP-ribose) polymerase 1 (PARP1) inhibition, which could be relevant to treatment of triple-negative tumors. To evaluate PARP1 inhibition in a realistic in vivo setting, we tested the PARP inhibitor AZD2281 in a genetically engineered mouse model (GEMM) for BRCA1-associated breast cancer. Treatment of tumor-bearing mice with AZD2281 inhibited tumor growth without signs of toxicity, resulting in strongly increased survival. Long-term treatment with AZD2281 in this model did result in the development of drug resistance, caused by up-regulation of Abcb1a / b genes encoding P-glycoprotein efflux pumps. This resistance to AZD2281 could be reversed by coadministration of the P-glycoprotein inhibitor tariquidar. Combination of AZD2281 with cisplatin or carboplatin increased the recurrence-free and overall survival, suggesting that AZD2281 potentiates the effect of these DNA-damaging agents. Our results demonstrate in vivo efficacy of AZD2281 against BRCA1-deficient breast cancer and illustrate how GEMMs of cancer can be used for preclinical evaluation of novel therapeutics and for testing ways to overcome or circumvent therapy resistance.
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Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy
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Self-citationSpecific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase
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DNA repair pathways as targets for cancer therapy
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Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers
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Resistance to therapy caused by intragenic deletion in BRCA2
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BRCA1 and BRCA2: 1994 and beyond
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Gorrini, C., Harris, I. S., & Mak, T. W. (2013) · Nature Reviews Drug Discovery · doi:10.1038/nrd4002 · Cited by 3,579
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Metadata
- Authors
- Rottenberg, S., Jaspers, J. E., Kersbergen, A., van der Burg, E., Nygren, A. O. H., Zander, S. A. L., Derksen, P. W. B., de Bruin, M., Zevenhoven, J., Lau, A., Boulter, R., Cranston, A., O'Connor, M. J., Martin, N. M. B., Borst, P., & Jonkers, J.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2008-11-04
- Volume
- 105
- Issue
- 44
- Pages
- 17079-17084
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2014599726
- Cited by
- 956
- References
- 7
- FWCI
- 22.94
- Type
- journal article
- Language
- en
- Open access
- green
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- The paper
- Rottenberg, S., Jaspers, J. E., Kersbergen, A., van der Burg, E., Nygren, A. O. H., Zander, S. A. L., Derksen, P. W. B., de Bruin, M., Zevenhoven, J., Lau, A., Boulter, R., Cranston, A., O'Connor, M. J., Martin, N. M. B., Borst, P., & Jonkers, J. (2008). High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.0806092105
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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