Division of Hematology-Oncology, and the Cancer Center, Department of Medicine, University of New Mexico Health Science Center, Albuquerque, NM, USA.
Blood. 2011 Jun 9;117(23):6074-82. doi: 10.1182/blood-2011-01-313734. Epub 2011 Mar 25.
Because cancer at its origin must acquire permanent genomic mutations, it is by definition a disease of DNA repair. Yet for cancer cells to replicate their DNA and divide, which is the fundamental phenotype of cancer, multiple DNA repair pathways are required. This produces a paradox for the cancer cell, where its origin is at the same time its weakness. To overcome this difficulty, a cancer cell often becomes addicted to DNA repair pathways other than the one that led to its initial mutability. The best example of this is in breast or ovarian cancers with mutated BRCA1 or 2, essential components of a repair pathway for repairing DNA double-strand breaks. Because replicating DNA requires repair of DNA double-strand breaks, these cancers have become reliant on another DNA repair component, PARP1, for replication fork progression. The inhibition of PARP1 in these cells results in catastrophic double-strand breaks during replication, and ultimately cell death. The exploitation of the addiction of cancer cells to a DNA repair pathway is based on synthetic lethality and has wide applicability to the treatment of many types of malignancies, including those of hematologic origin. There is a large number of novel compounds in clinical trials that use this mechanism for their antineoplastic activity, making synthetic lethality one of the most important new concepts in recent drug development.
由于癌症在其起源时必须获得永久性的基因组突变，因此从定义上讲，它是一种 DNA 修复疾病。然而，为了使癌细胞复制其 DNA 并分裂，这是癌症的基本表型，需要多种 DNA 修复途径。这就给癌细胞带来了一个悖论，因为其起源同时也是其弱点。为了克服这一困难，癌细胞通常会沉迷于导致其最初易变性的途径以外的其他 DNA 修复途径。最好的例子是在乳腺癌或卵巢癌中，BRCA1 或 BRCA2 发生突变，这是修复 DNA 双链断裂的修复途径的重要组成部分。由于复制 DNA 需要修复 DNA 双链断裂，因此这些癌症已经依赖于另一种 DNA 修复成分 PARP1 来进行复制叉的进展。PARP1 的抑制会导致复制过程中灾难性的双链断裂，并最终导致细胞死亡。利用癌细胞对 DNA 修复途径的依赖是基于合成致死性的，并且广泛适用于治疗许多类型的恶性肿瘤，包括血液起源的恶性肿瘤。目前有大量的新型化合物正在临床试验中，利用这种机制发挥抗肿瘤活性，使合成致死性成为最近药物开发中最重要的新概念之一。
