靶向胸部癌中的DNA损伤反应缺陷
Targeting DNA Damage Response Deficiency in Thoracic Cancers
DOI 原文链接
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影响因子:14.4
分区:医学1区 Top / 药学1区 毒理学1区
发表日期:2024 Sep
作者:
Aleksandra Bzura, Jake B Spicer, Sean Dulloo, Timothy A Yap, Dean A Fennell
DOI:
10.1007/s40265-024-02066-9
摘要
胸部癌包括非小细胞肺癌（NSCLC）、小细胞肺癌（SCLC）和恶性胸膜间皮瘤（MPM）。总体而言，它们是全球致死率最高的恶性肿瘤之一。基因组不稳定性是癌症的普遍特征，推动突变和肿瘤进化。DNA损伤反应（DDR）基因的缺陷会放大基因组不稳定性。由BRCA1/BRCA2失活引起的同源重组缺陷（HRD）已成为乳腺癌、卵巢癌以及前列腺癌和胰腺癌中利用多聚ADP-核糖聚合酶（PARP）抑制剂的合成致死策略的基础。然而，DDR缺陷及其治疗潜力在胸部癌中的研究较少。新兴证据表明，一部分胸部癌可能具有DDR缺陷，因此可以通过DDR药物有效靶向。本文回顾了当前关于胸部癌中DDR的证据，讨论了在实现临床益处方面的挑战与前景。
Abstract
Thoracic cancers comprise non-small cell lung cancers (NSCLCs), small cell lung cancers (SCLCs) and malignant pleural mesotheliomas (MPM). Collectively, they account for the highest rate of death from malignancy worldwide. Genomic instability is a universal feature of cancer, which fuels mutations and tumour evolution. Deficiencies in DNA damage response (DDR) genes amplify genomic instability. Homologous recombination deficiency (HRD), resulting from BRCA1/BRCA2 inactivation, is exploited for therapeutic synthetic lethality with poly-ADP ribose polymerase (PARP) inhibitors in breast and ovarian cancers, as well as in prostate and pancreatic cancers. However, DDR deficiency and its therapeutic implications are less well established in thoracic cancers. Emerging evidence suggests that a subset of thoracic cancers may harbour DDR deficiency and may, thus, be effectively targeted with DDR agents. Here, we review the current evidence surrounding DDR in thoracic cancers and discuss the challenges and promise for achieving clinical benefit with such therapeutics.