Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Department of Mathematics, University of Athens, Greece.
Cancer Treat Rev. 2016 Jul;48:8-19. doi: 10.1016/j.ctrv.2016.05.004. Epub 2016 May 24.
Preclinical evidence has been accumulating on the impact of the DNA repair status on the sensitivity/resistance to anticancer agents in different tumor types, including lung cancer. The possibility to predict the response to therapy, and specifically to platinum agents, based on tumor specific DNA repair functionality would enable to tailor its use only in those patients with maximum chances to respond, avoiding the burden of toxicity in those ones with lesser chances. We here reviewed the clinical evidence on the prognostic role of DNA repair markers and/or functional assays in predicting the response to a platinum-based chemotherapy in lung cancer patients. Consequently, we focused on those proteins involved in pathways repairing platinum induced DNA inter-strand and intra-strand crosslinks. Most promising clinical trials targeting the nucleotide repair protein ERCC1 in non-small cell lung cancer later on suffered from serious drawbacks. Nevertheless, these results spurred a variety of preclinical studies on a multitude of alternative DNA repair markers. However so far, no one of the analyzed DNA repair markers can be considered a reliable and mature biomarker for selecting patients. We discuss the reasons for such failure which discloses novel strategies for the future.
临床前证据不断积累，表明 DNA 修复状态对不同肿瘤类型（包括肺癌）中抗癌药物的敏感性/耐药性有影响。基于肿瘤特定的 DNA 修复功能来预测治疗反应，特别是预测铂类药物的反应，这将使我们能够仅在那些有最大反应机会的患者中使用铂类药物，避免在那些反应机会较小的患者中承受毒性的负担。我们在这里回顾了 DNA 修复标志物和/或功能测定在预测肺癌患者铂类化疗反应中的预后作用的临床证据。因此，我们重点关注那些参与修复铂诱导的 DNA 链间和链内交联的途径的蛋白质。针对非小细胞肺癌中核苷酸修复蛋白 ERCC1 的最有前途的临床试验后来遇到了严重的缺陷。然而，这些结果激发了大量针对多种替代 DNA 修复标志物的临床前研究。然而，到目前为止，没有一种分析的 DNA 修复标志物可以被认为是选择患者的可靠和成熟的生物标志物。我们讨论了导致这种失败的原因，这为未来揭示了新的策略。
