DNA damage repair in glioblastoma: current perspectives on its role in tumour progression, treatment resistance and PIKKing potential therapeutic targets.
Blood-brain barrier
DNA damage response, DNA repair
Glioblastoma
PIKK inhibitor
Treatment resistance
Journal
Cellular oncology (Dordrecht)
ISSN: 2211-3436
Titre abrégé: Cell Oncol (Dordr)
Pays: Netherlands
ID NLM: 101552938
Informations de publication
Date de publication:
Oct 2021
Oct 2021
Historique:
received:
21
12
2020
accepted:
17
05
2021
pubmed:
1
6
2021
medline:
8
2
2022
entrez:
31
5
2021
Statut:
ppublish
Résumé
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.
Sections du résumé
BACKGROUND
BACKGROUND
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.
CONCLUSIONS
CONCLUSIONS
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.
Identifiants
pubmed: 34057732
doi: 10.1007/s13402-021-00613-0
pii: 10.1007/s13402-021-00613-0
doi:
Substances chimiques
Antineoplastic Agents, Alkylating
0
Temozolomide
YF1K15M17Y
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
961-981Informations de copyright
© 2021. Crown.
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