Journal
CANCER DISCOVERY
Volume 3, Issue 1, Pages 68-81Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-12-0049
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Funding
- Netherlands Organization for Scientific Research [NWO-Toptalent 021.002.104, NWO-VIDI-91711302]
- Dutch Cancer Society [NKI 2006-3566, NKI 2007-3772, NKI 2009-4303, NKI 2011-5220]
- European Union (EU) [037665-CHEMORES, 260791-Eurocan-Platform]
- CTMM Breast Care
- NKI-AVL Cancer Systems Biology Centre
- NATIONAL CANCER INSTITUTE [P30CA072720, ZIABC011078] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [ZICAI001051] Funding Source: NIH RePORTER
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Inhibition of PARP is a promising therapeutic strategy for homologous recombination-deficient tumors, such as BRCA1-associated cancers. We previously reported that BRCA1-deficient mouse mammary tumors may acquire resistance to the clinical PARP inhibitor (PARPi) olaparib through activation of the P-glycoprotein drug efflux transporter. Here, we show that tumorspecific genetic inactivation of P-glycoprotein increases the long-term response of BRCA1-deficient mouse mammary tumors to olaparib, but these tumors eventually developed PARPi resistance. In a fraction of cases, this resistance is caused by partial restoration of homologous recombination due to somatic loss of 53BP1. Importantly, PARPi resistance was minimized by long-term treatment with the novel PARP inhibitor AZD2461, which is a poor P-glycoprotein substrate. Together, our data suggest that restoration of homologous recombination is an important mechanism for PARPi resistance in BRCA1-deficient mammary tumors and that the risk of relapse of BRCA1-deficient tumors can be effectively minimized by using optimized PARP inhibitors.
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