title: Loss of 53BP1 causes PARP inhibitor resistance in Brca1-mutated mouse mammary tumors.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Janneke E
authors.initials: JE
authors.lastname: Jaspers
authors.forename: Ariena
authors.initials: A
authors.lastname: Kersbergen
authors.forename: Ute
authors.initials: U
authors.lastname: Boon
authors.forename: Wendy
authors.initials: W
authors.lastname: Sol
authors.forename: Liesbeth
authors.initials: L
authors.lastname: van Deemter
authors.forename: Serge A
authors.initials: SA
authors.lastname: Zander
authors.forename: Rinske
authors.initials: R
authors.lastname: Drost
authors.forename: Ellen
authors.initials: E
authors.lastname: Wientjens
authors.forename: Jiuping
authors.initials: J
authors.lastname: Ji
authors.forename: Amal
authors.initials: A
authors.lastname: Aly
authors.forename: James H
authors.initials: JH
authors.lastname: Doroshow
authors.forename: Aaron
authors.initials: A
authors.lastname: Cranston
authors.forename: Niall M B
authors.initials: NM
authors.lastname: Martin
authors.forename: Alan
authors.initials: A
authors.lastname: Lau
authors.forename: Mark J
authors.initials: MJ
authors.lastname: O'Connor
authors.forename: Shridar
authors.initials: S
authors.lastname: Ganesan
authors.forename: Piet
authors.initials: P
authors.lastname: Borst
authors.forename: Jos
authors.initials: J
authors.lastname: Jonkers
authors.forename: Sven
authors.initials: S
authors.lastname: Rottenberg
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000172:deficiency; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019313:BRCA1 Protein / Q000235:genetics; D045744:Cell Line, Tumor; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics*; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy; D051379:Mice; D009154:Mutation; D010793:Phthalazines / Q000627:therapeutic use*; D010879:Piperazines / Q000627:therapeutic use*; D010880:Piperidines / Q000627:therapeutic use*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; C000609611:AZD2461; D000970:Antineoplastic Agents; D019313:BRCA1 Protein; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D010793:Phthalazines; D010879:Piperazines; D010880:Piperidines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C498302:Trp53bp1 protein, mouse; D000071857:Tumor Suppressor p53-Binding Protein 1; C531550:olaparib