PT  - JOURNAL ARTICLE
AU  - Jaspers, Janneke E.
AU  - Kersbergen, Ariena
AU  - Boon, Ute
AU  - Sol, Wendy
AU  - van Deemter, Liesbeth
AU  - Zander, Serge A.
AU  - Drost, Rinske
AU  - Wientjens, Ellen
AU  - Ji, Jiuping
AU  - Aly, Amal
AU  - Doroshow, James H.
AU  - Cranston, Aaron
AU  - Martin, Niall M.B.
AU  - Lau, Alan
AU  - O'Connor, Mark J.
AU  - Ganesan, Shridar
AU  - Borst, Piet
AU  - Jonkers, Jos
AU  - Rottenberg, Sven
TI  - Loss of 53BP1 Causes PARP Inhibitor Resistance in <em>Brca1</em>-Mutated Mouse Mammary Tumors
AID  - 10.1158/2159-8290.CD-12-0049
DP  - 2013 Jan 01
TA  - Cancer Discovery
PG  - 68--81
VI  - 3
IP  - 1
4099  - http://cancerdiscovery.aacrjournals.org/content/3/1/68.short
4100  - http://cancerdiscovery.aacrjournals.org/content/3/1/68.full
SO  - CANCER DISCOVERY2013 Jan 01; 3
AB  - 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 tumor-specific 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. Significance: In this study, we show that loss of 53BP1 causes resistance to PARP inhibition in mouse mammary tumors that are deficient in BRCA1. We hypothesize that low expression or absence of 53BP1 also reduces the response of patients with BRCA1-deficient tumors to PARP inhibitors. Cancer Discov; 3(1); 68–81. ©2012 AACR. See related commentary by Fojo and Bates, p. 20 This article is highlighted in the In This Issue feature, p. 1