New Drugs Development Unit, Service of Medical Oncology, Oncology Institute of Southern Switzerland (IOSI), EOC, Bellinzona, Switzerland.
New Drugs Development Unit, Service of Medical Oncology, Oncology Institute of Southern Switzerland (IOSI), EOC, Bellinzona, Switzerland.
Crit Rev Oncol Hematol. 2021 Dec;168:103539. doi: 10.1016/j.critrevonc.2021.103539. Epub 2021 Nov 18.
Cancer derives from alterations of pathways responsible for cell survival, differentiation and proliferation. Dysfunctions of mechanisms protecting genome integrity can promote oncogenesis but can also be exploited as therapeutic target. Poly-ADP-Ribose-Polymerase (PARP)-inhibitors, the first approved targeted agents able to tackle DNA damage response (DDR), have demonstrated antitumor activity, particularly when homologous recombination impairment is present. Despite the relevant results achieved, a large proportion of patients fail to obtain durable responses. The development of innovative treatments, able to overcome resistance and ensure long-lasting benefit for a wider population is still an unmet need. Moreover, improvement in biomarker assays is necessary to properly identify patients who can benefit from DDR targeting agents. Here we summarize the main DDR pathways, explain the current role of PARP inhibitors in cancer therapy and illustrate new therapeutic strategies targeting the DDR, focusing on the combinations of PARP inhibitors with other agents and on cell-cycle checkpoint inhibitors.
癌症源于负责细胞存活、分化和增殖的通路改变。保护基因组完整性的机制功能障碍可促进肿瘤发生，但也可被作为治疗靶点加以利用。聚 ADP-核糖聚合酶（PARP）抑制剂是首批被批准的能够靶向 DNA 损伤反应（DDR）的靶向药物，已显示出抗肿瘤活性，特别是在同源重组缺陷存在时。尽管取得了相关的研究成果，但仍有很大一部分患者无法获得持久的缓解。开发能够克服耐药性并为更广泛人群提供持久获益的创新疗法仍然是一个未满足的需求。此外，还需要改进生物标志物检测方法，以便正确识别能够从 DDR 靶向药物中获益的患者。在这里，我们总结了主要的 DDR 通路，解释了 PARP 抑制剂在癌症治疗中的当前作用，并说明了针对 DDR 的新治疗策略，重点介绍了 PARP 抑制剂与其他药物的联合应用以及细胞周期检查点抑制剂。
