title: High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs.
abstract: 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.
authors.affiliation: Division of Molecular Biology and Centre for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Sven
authors.initials: S
authors.lastname: Rottenberg
authors.forename: Janneke E
authors.initials: JE
authors.lastname: Jaspers
authors.forename: Ariena
authors.initials: A
authors.lastname: Kersbergen
authors.forename: Eline
authors.initials: E
authors.lastname: van der Burg
authors.forename: Anders O H
authors.initials: AO
authors.lastname: Nygren
authors.forename: Serge A L
authors.initials: SA
authors.lastname: Zander
authors.forename: Patrick W B
authors.initials: PW
authors.lastname: Derksen
authors.forename: Michiel
authors.initials: M
authors.lastname: de Bruin
authors.forename: John
authors.initials: J
authors.lastname: Zevenhoven
authors.forename: Alan
authors.initials: A
authors.lastname: Lau
authors.forename: Robert
authors.initials: R
authors.lastname: Boulter
authors.forename: Aaron
authors.initials: A
authors.lastname: Cranston
authors.forename: Mark J
authors.initials: MJ
authors.lastname: O'Connor
authors.forename: Niall M B
authors.initials: NM
authors.lastname: Martin
authors.forename: Piet
authors.initials: P
authors.lastname: Borst
authors.forename: Jos
authors.initials: J
authors.lastname: Jonkers
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D047072:Aromatase Inhibitors / Q000627:therapeutic use; D019313:BRCA1 Protein / Q000235:genetics*; D002945:Cisplatin / Q000627:therapeutic use; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D010793:Phthalazines / Q000627:therapeutic use*; D010879:Piperazines / Q000627:therapeutic use*; D017671:Platinum Compounds / Q000627:therapeutic use*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D019313:BRCA1 Protein; D010793:Phthalazines; D010879:Piperazines; D017671:Platinum Compounds; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D002945:Cisplatin; C531550:olaparib