High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs
High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs
复制标题
DOI：
10.1073/pnas.0806092105
复制
发表时间：
2008-11-04
影响因子：
11.1
通讯作者：
Jonkers, Jos
中科院分区：
文献类型：
--
作者：
Rottenberg, Sven;Jaspers, Janneke E.;Jonkers, Jos
尽管靶向特异性药物可用于治疗ERBB 2过表达和激素受体阳性乳腺癌，但对于激素受体和ERBB 2阴性（“三阴性”）乳腺癌，没有定制的治疗方法。三阴性肿瘤占所有乳腺癌的15%，并且经常通过同源重组（HR）在DNA双链断裂修复中存在缺陷，例如BRCA 1功能障碍。BRCA 1基因缺陷细胞的DNA修复缺陷特征赋予了对聚（ADP-核糖）聚合酶1（PARP 1）抑制的敏感性，这可能与三阴性肿瘤的治疗有关。为了在现实的体内环境中评估PARP 1抑制，我们在BRCA 1相关乳腺癌的基因工程小鼠模型（GEMM）中测试了PARP抑制剂AZD 2281。用AZD 2281治疗荷瘤小鼠可抑制肿瘤生长而无毒性迹象，导致存活率大幅增加。在该模型中，AZD 2281长期给药确实导致了耐药性的发生，这是由编码P-糖蛋白外排泵的Abcb 1a/B基因上调引起的。这种对AZD 2281的耐药性可通过联合P-糖蛋白抑制剂tariquidar逆转。AZD 2281与顺铂或卡铂联合使用增加了无复发和总生存期，表明AZD 2281增强了这些DNA损伤剂的作用。我们的结果证明了AZD 2281对BRCA 1缺陷乳腺癌的体内疗效，并说明了癌症的GEMM如何用于新型疗法的临床前评估以及测试克服或规避治疗耐药性的方法。
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-cleficient 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 coad ministration 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.