Boussios Stergios, Rassy Elie, Moschetta Michele, Ghose Aruni, Adeleke Sola, Sanchez Elisabet, Sheriff Matin, Chargari Cyrus, Pavlidis Nicholas
Department of Medical Oncology, Medway NHS Foundation Trust, Windmill Road, Gillingham ME7 5NY, UK.
Faculty of Life Sciences & Medicine, School of Cancer & Pharmaceutical Sciences, King's College London, London SE1 9RT, UK.
Cancers (Basel). 2022 Aug 11;14(16):3888. doi: 10.3390/cancers14163888.
DNA damage repair (DDR) defects are common in different cancer types, and these alterations can be exploited therapeutically. Epithelial ovarian cancer (EOC) is among the tumours with the highest percentage of hereditary cases. and predisposing pathogenic variants (PVs) were the first to be associated with EOC, whereas additional genes comprising the homologous recombination (HR) pathway have been discovered with DNA sequencing technologies. The incidence of DDR alterations among patients with metastatic prostate cancer is much higher compared to those with localized disease. Genetic testing is playing an increasingly important role in the treatment of patients with ovarian and prostate cancer. The development of poly (ADP-ribose) polymerase (PARP) inhibitors offers a therapeutic strategy for patients with EOC. One of the mechanisms of PARP inhibitors exploits the concept of synthetic lethality. Tumours with or mutations are highly sensitive to PARP inhibitors. Moreover, the synthetic lethal interaction may be exploited beyond germline mutations in the context of HR deficiency, and this is an area of ongoing research. PARP inhibitors are in advanced stages of development as a treatment for metastatic castration-resistant prostate cancer. However, there is a major concern regarding the need to identify reliable biomarkers predictive of treatment response. In this review, we explore the mechanisms of DDR, the potential for genomic analysis of ovarian and prostate cancer, and therapeutics of PARP inhibitors, along with predictive biomarkers.
DNA损伤修复（DDR）缺陷在不同类型的癌症中很常见，这些改变可用于治疗。上皮性卵巢癌（EOC）是遗传性病例占比最高的肿瘤之一。BRCA1和BRCA2是最早与EOC相关的易感致病变体（PVs），而随着DNA测序技术的发展，又发现了包括同源重组（HR）途径在内的其他基因。与局限性前列腺癌患者相比，转移性前列腺癌患者中DDR改变的发生率要高得多。基因检测在卵巢癌和前列腺癌患者的治疗中发挥着越来越重要的作用。聚（ADP-核糖）聚合酶（PARP）抑制剂的开发为EOC患者提供了一种治疗策略。PARP抑制剂的作用机制之一利用了合成致死的概念。具有BRCA1或BRCA2突变的肿瘤对PARP抑制剂高度敏感。此外，在HR缺陷的情况下，合成致死相互作用可能不仅适用于种系BRCA突变，这是一个正在进行研究的领域。PARP抑制剂作为转移性去势抵抗性前列腺癌的治疗药物正处于开发的后期阶段。然而，对于需要识别预测治疗反应的可靠生物标志物存在重大担忧。在这篇综述中，我们探讨了DDR的机制、卵巢癌和前列腺癌基因组分析的潜力、PARP抑制剂的治疗方法以及预测性生物标志物。
