High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs.
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.
Rottenberg
Sven
S
Division of Molecular Biology and Centre for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Jaspers
Janneke E
JE
Kersbergen
Ariena
A
van der Burg
Eline
E
Nygren
Anders O H
AO
Zander
Serge A L
SA
Derksen
Patrick W B
PW
de Bruin
Michiel
M
Zevenhoven
John
J
Lau
Alan
A
Boulter
Robert
R
Cranston
Aaron
A
O'Connor
Mark J
MJ
Martin
Niall M B
NM
Borst
Piet
P
Jonkers
Jos
J
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
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