Poly(ADP-Ribose) polymerase inhibition: "targeted" therapy for triple-negative breast cancer.
Poly(ADP-Ribose) polymerase inhibition: "targeted" therapy for triple-negative breast cancer.
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DOI：
10.1158/1078-0432.ccr-10-0939
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发表时间：
2010-10-01
期刊：
影响因子：
--
通讯作者：
Carey LA
中科院分区：
文献类型：
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作者：
Anders CK;Winer EP;Ford JM;Dent R;Silver DP;Sledge GW;Carey LA
与内分泌敏感和 HER2 阳性乳腺癌相比，缺乏能够治疗晚期三阴性乳腺癌 (TNBC) 的新型药物。 PARP（聚（腺苷二磷酸 [ADP]-核糖）聚合酶）抑制剂正在成为治疗 TNBC 最有前途的“靶向”疗法之一，其预期“目标”是 DNA 修复。 PARP 是参与多种细胞过程（包括 DNA 修复）的酶家族。 TNBC 与 BRCA 突变乳腺癌具有多种临床病理特征，后者含有功能失调的 DNA 修复机制。研究人员推测，PARP 抑制与 BRCA 依赖性机制导致的 DNA 修复丧失相结合，将导致合成致死性和增加细胞死亡。这一假设已在临床前模型和在 BRCA 缺陷型和 TNBC 中测试 PARP 抑制剂的临床试验中得到证实。本综述的重点将包括概述评估 TNBC 中 PARP 抑制剂的临床前基本原理、该新型治疗类别的假定作用机制、晚期乳腺癌（TNBC 和 BRCA 缺陷）中 PARP 抑制的几项有影响力的临床试验的有希望的结果、对 PARP 抑制剂获得性耐药的拟议机制，最后总结 PARP 抑制剂在乳腺癌治疗中的发展当前面临的挑战和未来方向。
In contrast to endocrine-sensitive and HER2-positive breast cancer, novel agents capable of treating advanced triple negative breast cancer (TNBC) are lacking. PARP (Poly-(adenosine diphosphate [ADP]-ribose) polymerase) inhibitors are emerging as one of the most promising ‘targeted’ therapeutics to treat TNBC, with the intended ‘target’ being DNA repair. PARP's are a family of enzymes involved in multiple cellular processes including DNA repair. TNBC shares multiple clinico-pathologic features with BRCA-mutated breast cancers which harbor dysfunctional DNA repair mechanisms. Investigators hypothesized PARP inhibition, in conjunction with the loss of DNA-repair via BRCA-dependent mechanisms, would result in synthetic lethality and augmented cell death. This hypothesis has borne out in both preclinical models and in clinical trials testing PARP inhibitors in both BRCA-deficient and TNBC. The focus of this review will include an overview of the preclinical rationale for evaluating PARP inhibitors in TNBC, the presumed mechanism of action of this novel therapeutic class, promising results from several influential clinical trials of PARP inhibition in advanced breast cancer (both TNBC and BRCA-deficient), proposed mechanisms of acquired resistance to PARP inhibitors, and, finally, conclude with current challenges and future directions for the development of PARP inhibitors in the treatment of breast cancer.