Rottenberg Sven, Jaspers Janneke E, Kersbergen Ariena, van der Burg Eline, Nygren Anders O H, Zander Serge A L, Derksen Patrick W B, de Bruin Michiel, Zevenhoven John, Lau Alan, Boulter Robert, Cranston Aaron, O'Connor Mark J, Martin Niall M B, Borst Piet, Jonkers Jos
Division of Molecular Biology and Centre for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):17079-84. doi: 10.1073/pnas.0806092105. Epub 2008 Oct 29.
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.
虽然有针对ERBB2过表达和激素受体阳性乳腺癌的靶向药物，但对于激素受体和ERBB2阴性（“三阴性”）乳腺癌却没有量身定制的治疗方法。三阴性肿瘤占所有乳腺癌的15%，并且经常在通过同源重组（HR）进行DNA双链断裂修复时存在缺陷，比如BRCA1功能障碍。BRCA1缺陷细胞特有的DNA修复缺陷使其对聚（ADP - 核糖）聚合酶1（PARP1）抑制敏感，这可能与三阴性肿瘤的治疗相关。为了在实际的体内环境中评估PARP1抑制作用，我们在一种用于BRCA1相关乳腺癌的基因工程小鼠模型（GEMM）中测试了PARP抑制剂AZD2281。用AZD2281治疗荷瘤小鼠可抑制肿瘤生长且无毒性迹象，从而使生存率大幅提高。在该模型中用AZD2281长期治疗确实导致了耐药性的产生，这是由编码P - 糖蛋白外排泵的Abcb1a/b基因上调引起的。对AZD2281的这种耐药性可通过联合使用P - 糖蛋白抑制剂他林洛尔来逆转。AZD2281与顺铂或卡铂联合使用可提高无复发生存率和总生存率，这表明AZD2281可增强这些DNA损伤剂的作用。我们的结果证明了AZD2281对BRCA1缺陷型乳腺癌的体内疗效，并说明了癌症的基因工程小鼠模型可如何用于新型治疗药物的临床前评估以及测试克服或规避治疗耐药性的方法。
