University of Sydney, Sydney, New South Wales, Australia.
Genome Integrity Unit, Children's Medical Research Institute, University of Sydney, Sydney, New South Wales, Australia.
J Med Imaging Radiat Oncol. 2022 Jun;66(4):546-559. doi: 10.1111/1754-9485.13413. Epub 2022 Apr 23.
The DNA damage response (DDR) is a complex set of downstream pathways triggered in response to DNA damage to maintain genomic stability. Many tumours exhibit mutations which inactivate components of the DDR, making them prone to the accumulation of DNA defects. These can both facilitate the development of tumours and provide potential targets for novel therapeutic interventions. The inhibition of the DDR has been shown to induce radiosensitivity in certain cancers, rendering them susceptible to treatment with radiotherapy and improving the therapeutic window. Moreover, DDR defects are a strong predictor of patient response to immune checkpoint inhibition (ICI). The ability to target the DDR selectively has the potential to expand the tumour neoantigen repertoire, thus increasing tumour immunogenicity and facilitating a CD8+ T and NK cell response against cancer cells. Combinatorial approaches, which seek to integrate DDR inhibition with radiotherapy and immunotherapy, have shown promise in early trials. Further studies are necessary to understand these synergies and establish reliable biomarkers.
DNA 损伤反应 (DDR) 是一组复杂的下游途径，在 DNA 损伤时被触发，以维持基因组稳定性。许多肿瘤表现出的突变会使 DDR 的成分失活，从而容易积累 DNA 缺陷。这些缺陷既可以促进肿瘤的发展，也可以为新的治疗干预提供潜在的靶点。已经证明，抑制 DDR 可以在某些癌症中诱导放射敏感性，使它们容易受到放射治疗的影响，并改善治疗窗口。此外，DDR 缺陷是患者对免疫检查点抑制 (ICI) 反应的一个强有力的预测因子。选择性靶向 DDR 的能力有可能扩大肿瘤新抗原谱，从而增加肿瘤的免疫原性，并促进 CD8+T 和 NK 细胞对癌细胞的反应。寻求将 DDR 抑制与放射治疗和免疫治疗相结合的联合方法，在早期试验中显示出了前景。需要进一步的研究来理解这些协同作用并建立可靠的生物标志物。
