Liptay Martin, Barbosa Joana S, Rottenberg Sven
Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
Bern Center for Precision Medicine, University of Bern, Bern, Switzerland.
Front Oncol. 2020 May 5;10:670. doi: 10.3389/fonc.2020.00670. eCollection 2020.
Most cancers have lost a critical DNA damage response (DDR) pathway during tumor evolution. These alterations provide a useful explanation for the initial sensitivity of tumors to DNA-targeting chemotherapy. A striking example is dysfunctional homology-directed repair (HDR), e.g., due to inactivating mutations in and genes. Extensive efforts are being made to develop novel targeted therapies exploiting such an HDR defect. Inhibitors of poly(ADP-ribose) polymerase (PARP) are an instructive example of this approach. Despite the success of PARP inhibitors, the presence of primary or acquired therapy resistance remains a major challenge in clinical oncology. To move the field of precision medicine forward, we need to understand the precise mechanisms causing therapy resistance. Using preclinical models, various mechanisms underlying chemotherapy resistance have been identified. Restoration of HDR seems to be a prevalent mechanism but this does not explain resistance in all cases. Interestingly, some factors involved in DNA damage response (DDR) have independent functions in replication fork (RF) biology and their loss causes RF instability and therapy sensitivity. However, in BRCA-deficient tumors, loss of these factors leads to restored stability of RFs and acquired drug resistance. In this review we discuss the recent advances in the field of RF biology and its potential implications for chemotherapy response in DDR-defective cancers. Additionally, we review the role of DNA damage tolerance (DDT) pathways in maintenance of genome integrity and their alterations in cancer. Furthermore, we refer to novel tools that, combined with a better understanding of drug resistance mechanisms, may constitute a great advance in personalized diagnosis and therapeutic strategies for patients with HDR-deficient tumors.
大多数癌症在肿瘤发生发展过程中都丧失了关键的DNA损伤反应（DDR）途径。这些改变为肿瘤对靶向DNA的化疗药物的初始敏感性提供了合理的解释。一个显著的例子是功能失调的同源重组修复（HDR），例如，由于 和 基因的失活突变。人们正在广泛努力开发利用这种HDR缺陷的新型靶向疗法。聚（ADP - 核糖）聚合酶（PARP）抑制剂就是这种方法的一个典型例子。尽管PARP抑制剂取得了成功，但原发性或获得性治疗耐药性的存在仍然是临床肿瘤学中的一个重大挑战。为了推动精准医学领域向前发展，我们需要了解导致治疗耐药性的确切机制。利用临床前模型，已经确定了化疗耐药性的各种潜在机制。HDR的恢复似乎是一种普遍的机制，但这并不能解释所有情况下的耐药性。有趣的是，一些参与DNA损伤反应（DDR）的因子在复制叉（RF）生物学中具有独立功能，它们的缺失会导致RF不稳定和治疗敏感性。然而，在BRCA缺陷的肿瘤中，这些因子的缺失会导致RF稳定性恢复和获得性耐药。在这篇综述中，我们讨论了RF生物学领域的最新进展及其对DDR缺陷型癌症化疗反应的潜在影响。此外，我们回顾了DNA损伤耐受（DDT）途径在维持基因组完整性中的作用及其在癌症中的改变。此外，我们提及了一些新工具，结合对耐药机制的更好理解，这些工具可能会在HDR缺陷型肿瘤患者的个性化诊断和治疗策略方面取得重大进展。
