University of Leicester, NIHR Biomedical Research Centre and Robert Kilpatrick Clinical Sciences Building, Leicester, UK.
University Hospitals of Leicester NHS Trust, Leicester, UK.
Drugs. 2024 Sep;84(9):1025-1033. doi: 10.1007/s40265-024-02066-9. Epub 2024 Jul 13.
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.
胸部癌症包括非小细胞肺癌（NSCLC）、小细胞肺癌（SCLC）和恶性胸膜间皮瘤（MPM）。它们共同导致了全球最高的恶性肿瘤死亡率。基因组不稳定性是癌症的普遍特征，它会引发突变和肿瘤进化。DNA 损伤反应（DDR）基因缺陷会加剧基因组不稳定性。BRCA1/BRCA2 失活导致同源重组缺陷（HRD），这在乳腺癌和卵巢癌以及前列腺癌和胰腺癌中被用于与聚 ADP 核糖聚合酶（PARP）抑制剂的治疗性合成致死。然而，DDR 缺陷及其治疗意义在胸部癌症中尚未得到充分确立。新出现的证据表明，一部分胸部癌症可能存在 DDR 缺陷，因此可以用 DDR 药物有效地靶向这些缺陷。在这里，我们回顾了 DDR 在胸部癌症中的现有证据，并讨论了用这些治疗方法获得临床获益所面临的挑战和前景。
