Min Ahrum, Lee Kyung-Hun, Im Seock-Ah
Cancer Research Institute, Seoul National University, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea.
Department of Internal Medicine, Seoul National University Hospital, Cancer Research Institute, Seoul National University, Seoul, South Korea.
Adv Exp Med Biol. 2021;1187:159-179. doi: 10.1007/978-981-32-9620-6_8.
Cancer has been defined as a genetic disorder caused by the accumulation of genetic alterations, which result from various internal and external DNA damage that is left unrepaired. One of the main characteristics of cancer is a partial loss of DNA damage repair (DDR) pathway, resulting in increased DNA damage levels and replication stress. DDR inhibitors have been suggested as a new anticancer strategy, under the concept of synthetic lethality. The poly-(ADP-ribose) polymerase (PARP) inhibitor is the first DDR inhibitor to be used in clinical practice. PARP inhibitors have been tested in patients with BRCA1/2 germline mutations (gBRCA1/2mt) and shown robust clinical benefits in breast cancer with gBRCA1/2mt and serous ovarian cancer patients. The concept of synthetic lethality is not limited to gBRCAmt for PARP inhibitor, and discovering homologous recombination deficiency (HRD) markers beyond BRCA1/2 and identifying best candidates for DDR inhibitors are the active research areas. At the same time, various combinations of DDR inhibitors and other anticancer drugs are being tested in both preclinical and clinical studies. In addition, based on recent evidence of the immune-modulatory effect of PARP inhibitors, the combination of DDR inhibitors and immune checkpoint inhibitors is being actively investigated. Acquired resistance mechanism of DDR inhibitors, as well as defining best candidates and best combinations, would be future research topics for DDR inhibitors. Furthermore, it would also be crucial to establish a clinically relevant standardized method to detect HRD for future clinical use.
癌症被定义为一种由基因改变积累引起的基因紊乱，这些基因改变源于各种未得到修复的内源性和外源性DNA损伤。癌症的主要特征之一是DNA损伤修复（DDR）途径部分丧失，导致DNA损伤水平增加和复制应激。在合成致死性的概念下，DDR抑制剂已被提议作为一种新的抗癌策略。聚（ADP-核糖）聚合酶（PARP）抑制剂是首个用于临床实践的DDR抑制剂。PARP抑制剂已在携带BRCA1/2种系突变（gBRCA1/2mt）的患者中进行了测试，并在患有gBRCA1/2mt的乳腺癌和浆液性卵巢癌患者中显示出显著的临床益处。合成致死性的概念并不局限于PARP抑制剂的gBRCAmt，发现BRCA1/2以外的同源重组缺陷（HRD）标志物并确定DDR抑制剂的最佳候选物是活跃的研究领域。同时，DDR抑制剂与其他抗癌药物的各种联合正在临床前和临床研究中进行测试。此外，基于PARP抑制剂免疫调节作用的最新证据，DDR抑制剂与免疫检查点抑制剂的联合正在积极研究中。DDR抑制剂的获得性耐药机制，以及确定最佳候选物和最佳联合方案，将是DDR抑制剂未来的研究课题。此外，建立一种临床相关的标准化方法来检测HRD以供未来临床使用也至关重要。
