靶向 DNA 损伤反应和免疫检查点的抗肿瘤治疗。

Targeting DNA Damage Response and Immune Checkpoint for Anticancer Therapy.

机构信息

Department of Bioscience Technology, College of Health Science, Chang Jung Christian University, Tainan 711, Taiwan.

Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.

出版信息

Int J Mol Sci. 2022 Mar 17;23(6):3238. doi: 10.3390/ijms23063238.

DOI:10.3390/ijms23063238

PMID:35328658

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8952261/

Abstract

Deficiency in DNA damage response (DDR) genes leads to impaired DNA repair functions that will induce genomic instability and facilitate cancer development. However, alterations of DDR genes can serve as biomarkers for the selection of suitable patients to receive specific therapeutics, such as immune checkpoint blockade (ICB) therapy. In addition, certain altered DDR genes can be ideal therapeutic targets through adapting the mechanism of synthetic lethality. Recent studies indicate that targeting DDR can improve cancer immunotherapy by modulating the immune response mediated by cGAS-STING-interferon signaling. Investigations of the interplay of DDR-targeting and ICB therapies provide more effective treatment options for cancer patients. This review introduces the mechanisms of DDR and discusses their crucial roles in cancer therapy based on the concepts of synthetic lethality and ICB. The contemporary clinical trials of DDR-targeting and ICB therapies in breast, colorectal, and pancreatic cancers are included.

摘要

DNA 损伤反应 (DDR) 基因缺陷导致 DNA 修复功能受损，从而引发基因组不稳定并促进癌症发展。然而，DDR 基因的改变可以作为选择合适患者接受特定治疗的生物标志物，如免疫检查点阻断 (ICB) 治疗。此外，某些改变的 DDR 基因可以通过适应合成致死性的机制成为理想的治疗靶点。最近的研究表明，通过调节 cGAS-STING-干扰素信号介导的免疫反应，靶向 DDR 可以改善癌症免疫治疗。对 DDR 靶向和 ICB 治疗相互作用的研究为癌症患者提供了更有效的治疗选择。本综述介绍了 DDR 的机制，并基于合成致死性和 ICB 的概念讨论了它们在癌症治疗中的关键作用。还包括了针对乳腺癌、结直肠癌和胰腺癌的 DDR 靶向和 ICB 治疗的当代临床试验。