Lozinski Mathew, Bowden Nikola A, Graves Moira C, Fay Michael, Tooney Paul A
School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Newcastle, NSW, Australia.
Centre for Drug Repurposing and Medicines Research, University of Newcastle, Newcastle, NSW, Australia.
Cell Oncol (Dordr). 2021 Oct;44(5):961-981. doi: 10.1007/s13402-021-00613-0. Epub 2021 May 31.
The aggressive, invasive and treatment resistant nature of glioblastoma makes it one of the most lethal cancers in humans. Total surgical resection is difficult, and a combination of radiation and chemotherapy is used to treat the remaining invasive cells beyond the tumour border by inducing DNA damage and activating cell death pathways in glioblastoma cells. Unfortunately, recurrence is common and a major hurdle in treatment, often met with a more aggressive and treatment resistant tumour. A mechanism of resistance is the response of DNA repair pathways upon treatment-induced DNA damage, which enact cell-cycle arrest and repair of DNA damage that would otherwise cause cell death in tumour cells.
In this review, we discuss the significance of DNA repair mechanisms in tumour formation, aggression and treatment resistance. We identify an underlying trend in the literature, wherein alterations in DNA repair pathways facilitate glioma progression, while established high-grade gliomas benefit from constitutively active DNA repair pathways in the repair of treatment-induced DNA damage. We also consider the clinical feasibility of inhibiting DNA repair in glioblastoma and current strategies of using DNA repair inhibitors as agents in combination with chemotherapy, radiation or immunotherapy. Finally, the importance of blood-brain barrier penetrance when designing novel small-molecule inhibitors is discussed.
胶质母细胞瘤具有侵袭性、浸润性和对治疗耐药的特性，使其成为人类最致命的癌症之一。完全手术切除困难，放疗和化疗联合使用，通过诱导DNA损伤和激活胶质母细胞瘤细胞中的细胞死亡途径来治疗肿瘤边界以外的残留浸润性细胞。不幸的是，复发很常见，是治疗中的一个主要障碍，复发时肿瘤往往更具侵袭性且对治疗耐药。一种耐药机制是DNA修复途径对治疗诱导的DNA损伤的反应，这种反应会导致细胞周期停滞并修复DNA损伤，否则会导致肿瘤细胞死亡。
在本综述中，我们讨论了DNA修复机制在肿瘤形成、侵袭和治疗耐药中的意义。我们确定了文献中的一个潜在趋势，即DNA修复途径的改变促进胶质瘤进展，而既定的高级别胶质瘤在修复治疗诱导的DNA损伤时受益于组成性激活的DNA修复途径。我们还考虑了抑制胶质母细胞瘤中DNA修复的临床可行性以及使用DNA修复抑制剂作为与化疗、放疗或免疫疗法联合用药的当前策略。最后，讨论了设计新型小分子抑制剂时血脑屏障穿透性的重要性。
