Synthetic lethality of PARP inhibition in cancers lacking BRCA1 and BRCA2 mutations
Synthetic lethality of PARP inhibition in cancers lacking BRCA1 and BRCA2 mutations
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DOI：
10.4161/cc.10.8.15273
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发表时间：
2011-04-15
期刊：
影响因子：
4.3
通讯作者：
Reis-Filho, Jorge S.
中科院分区：
文献类型：
--
作者：
Dedes, Konstantin J.;Wilkerson, Paul M.;Reis-Filho, Jorge S.
利用合成致死性的概念，通过允许靶向功能丧失的遗传畸变，为靶向治疗的发展提供了新的机会。在具有BRCA 1或BRCA 2功能丧失的癌细胞中，其具有通过同源重组进行的DNA修复的缺陷，PARP 1酶活性的抑制导致单链断裂的积累，所述单链断裂转化为双链断裂，但不能通过同源重组进行修复。因此，PARP的抑制已被作为携带BRCA 1/2突变的癌症的新型靶向疗法而得到发展。然而，临床前和初步临床证据表明PARP抑制剂的潜在范围更广。已经表明，除BRCA 1/2之外，参与双链断裂修复的各种蛋白质的功能丧失在PARP抑制下是合成致死的。在人类癌症的一个子集中已经报告了这些基因的失活，因此可能构成PARP抑制的预测性生物标志物。在这里，我们讨论的证据表明，PARP抑制的临床应用可能比靶向BRCA 1/2生殖系突变携带者的癌症更广泛。
Utilizing the concept of synthetic lethality has provided new opportunities for the development of targeted therapies, by allowing the targeting of loss of function genetic aberrations. In cancer cells with BRCA1 or BRCA2 loss of function, which harbor deficiency of DNA repair by homologous recombination, inhibition of PARP1 enzymatic activity leads to an accumulation of single strand breaks that are converted to double strand breaks but cannot be repaired by homologous recombination. Inhibition of PARP has therefore been advanced as a novel targeted therapy for cancers harboring BRCA1/2 mutations. Preclinical and preliminary clinical evidence, however, suggests a potentially broader scope for PARP inhibitors. Loss of function of various proteins involved in double strand break repair other than BRCA1/2 has been suggested to be synthetically lethal with PARP inhibition. Inactivation of these genes has been reported in a subset of human cancers and might therefore constitute predictive biomarkers for PARP inhibition. Here we discuss the evidence that the clinical use of PARP inhibition may be broader than targeting of cancers in BRCA1/2 germ-line mutation carriers.