Department of Obstetrics and Gynecology, Ehime University Graduate School of Medicine, Toon, Japan.
Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Toon, Japan.
Cancer Sci. 2022 Sep;113(9):2943-2951. doi: 10.1111/cas.15477. Epub 2022 Jul 16.
PARP inhibitors (PARPis) were initially developed as DNA repair inhibitors that inhibit the catalytic activity of PARP1 and PARP2 and are expected to induce synthetic lethality in BRCA- or homologous recombination (HR)-deficient tumors. However, the clinical indications for PARPis are not necessarily limited to BRCA mutations or HR deficiency; BRCA wild-type and HR-proficient cancers can also derive some benefit from PARPis. These facts are interpretable by an additional primary antitumor mechanism of PARPis named PARP trapping, resulting from the stabilization of PARP-DNA complexes. Favorable response to platinum derivatives (cisplatin and carboplatin) in preceding treatment is used as a clinical biomarker for some PARPis, implying that sensitivity factors for platinum derivatives and PARPis are mainly common. Such common sensitivity factors include not only HR defects (HRD) but also additional factors. One of them is Schlafen 11 (SLFN11), a putative DNA/RNA helicase, that sensitizes cancer cells to a broad type of DNA-damaging agents, including platinum and topoisomerase inhibitors. Mechanistically, SLFN11 induces a lethal replication block in response to replication stress (ie, DNA damage). As SLFN11 acts upon replication stress, trapping PARPis can activate SLFN11. Preclinical models show the importance of SLFN11 in PARPi sensitivity. However, the relevance of SLFN11 in PARPi response is less evident in clinical data compared with the significance of SLFN11 for platinum sensitivity. In this review, we consider the reasons for variable indications of PARPis resulting from clinical outcomes and review the mechanisms of action for PARPis as anticancer agents.
聚腺苷二磷酸核糖聚合酶抑制剂（PARPi）最初被开发为 DNA 修复抑制剂，可抑制 PARP1 和 PARP2 的催化活性，并有望在 BRCA 或同源重组（HR）缺陷型肿瘤中诱导合成致死。然而，PARPi 的临床适应证不一定局限于 BRCA 突变或 HR 缺陷；BRCA 野生型和 HR 功能正常的癌症也可以从 PARPi 中获得一些益处。PARPi 的另一个主要抗肿瘤机制——PARP 捕获，可以解释这些事实，这是由于 PARP-DNA 复合物的稳定化。在先前的治疗中对铂衍生物（顺铂和卡铂）的有利反应被用作某些 PARPi 的临床生物标志物，这意味着铂衍生物和 PARPi 的敏感性因素主要是共同的。这些共同的敏感性因素不仅包括 HR 缺陷（HRD），还包括其他因素。其中之一是 Schlafen 11（SLFN11），一种假定的 DNA/RNA 解旋酶，可使癌细胞对包括铂类和拓扑异构酶抑制剂在内的广泛类型的 DNA 损伤剂敏感。从机制上讲，SLFN11 会在复制应激（即 DNA 损伤）时引发致命的复制阻滞。由于 SLFN11 作用于复制应激，因此 PARPi 捕获可以激活 SLFN11。临床前模型表明 SLFN11 在 PARPi 敏感性中的重要性。然而，与 SLFN11 对铂类敏感性的重要性相比，SLFN11 在 PARPi 反应中的相关性在临床数据中并不那么明显。在这篇综述中，我们考虑了导致 PARPi 临床结果的不同适应证的原因，并回顾了 PARPi 作为抗癌药物的作用机制。
