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.breast cancer ͉ drug resistance ͉ P-glycoprotein ͉ GEMM ͉ DNA repair P oly(ADP-ribose) polymerase 1 (PARP1) is involved in surveillance and maintenance of genome integrity and functions as a key molecule in the repair of DNA single-strand breaks (SSBs) (1-3). Inactivation of SSB repair by PARP1 inhibition during S-phase induces DNA double-strand breaks (DSBs) and may thus confer synthetic lethality to cells with defective homology-directed DSB repair (4, 5). Mutations in BRCA1 or BRCA2 predispose to hereditary breast and ovarian cancer, which accounts for 3-5% of all breast cancers and a greater proportion of ovarian cancers (6). BRCA1 and BRCA2 function is critical for homologous recombination (HR) (6, 7), and BRCA-deficient cells appear to be highly sensitive to PARP inhibition, resulting in increased genomic instability, cell cycle arrest, and apoptosis (4, 5). PARP1 inhibition might, therefore, be a specific therapy for cancers with defects in BRCA1/2 or other HR pathway components (clinically relevant PARP inhibitors are reviewed in ref. 8). Recently, Donawho et al. (9) have reported that the PARP inhibitor ABT-888 in combination with platinum drugs or cyclophosphamide, but not alone, causes regression of BRCA1-deficient MX-1 xenografts. However, this study uses only a single BRCA1-mutated tumor line without isogenic controls to address the impact of BRCA1 mutation on response...

Poly(ADP-ribose) polymerase activation is an immediate cellular response to metabolic-, chemical-, or ionizing radiation-induced DNA damage and represents a new target for cancer therapy. In this article, we disclose a novel series of substituted 4-benzyl-2 H-phthalazin-1-ones that possess high inhibitory enzyme and cellular potency for both PARP-1 and PARP-2. Optimized compounds from the series also demonstrate good pharmacokinetic profiles, oral bioavailability, and activity in vivo in an SW620 colorectal cancer xenograft model. 4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2 H-phthalazin-1-one (KU-0059436, AZD2281) 47 is a single digit nanomolar inhibitor of both PARP-1 and PARP-2 that shows standalone activity against BRCA1-deficient breast cancer cell lines. Compound 47 is currently undergoing clinical development for the treatment of BRCA1- and BRCA2-defective cancers.

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