Targeting TOPK sensitises tumour cells to radiation-induced damage by enhancing replication stress

T-LAK-originated protein kinase (TOPK) overexpression is a feature of multiple cancers, yet is absent from most phenotypically normal tissues. As such, TOPK expression profiling and the development of TOPK-targeting pharmaceutical agents have raised hopes for its future potential in the development...

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Veröffentlicht in:Cell death and differentiation Jg. 28; H. 4; S. 1333 - 1346
Hauptverfasser: Herbert, Katharine J, Puliyadi, Rathi, Prevo, Remko, Rodriguez-Berriguete, Gonzalo, Ryan, Anderson, Ramadan, Kristijan, Higgins, Geoff S
Format: Journal Article
Sprache:Englisch
Veröffentlicht: England Nature Publishing Group 01.04.2021
Schlagworte:
Animals
Apoptosis - drug effects
Apoptosis - radiation effects
cdc25 Phosphatases - drug effects
cdc25 Phosphatases - genetics
cdc25 Phosphatases - radiation effects
Cell Line, Tumor
Checkpoint Kinase 1 - drug effects
Checkpoint Kinase 1 - genetics
Checkpoint Kinase 1 - radiation effects
CHK1 protein
Deoxyribonucleic acid
DNA
DNA biosynthesis
DNA damage
Drug development
Female
Humans
Kinases
Lung cancer
Lung Neoplasms - metabolism
Lung Neoplasms - radiotherapy
Mice
Mice, Nude
Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors
Mitogen-Activated Protein Kinase Kinases - genetics
Mitogen-Activated Protein Kinase Kinases - metabolism
Protein kinase
Protein Kinase Inhibitors - pharmacology
Quinolones - pharmacology
Radiation
Radiation Tolerance - drug effects
Radiation Tolerance - genetics
S phase
Signal Transduction
Single-stranded DNA
Solid tumors
Survival Rate
Xenograft Model Antitumor Assays
Xenografts
ISSN:1350-9047, 1476-5403, 1476-5403
Online-Zugang:Volltext
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Zusammenfassung:T-LAK-originated protein kinase (TOPK) overexpression is a feature of multiple cancers, yet is absent from most phenotypically normal tissues. As such, TOPK expression profiling and the development of TOPK-targeting pharmaceutical agents have raised hopes for its future potential in the development of targeted therapeutics. Results presented in this paper confirm the value of TOPK as a potential target for the treatment of solid tumours, and demonstrate the efficacy of a TOPK inhibitor (OTS964) when used in combination with radiation treatment. Using H460 and Calu-6 lung cancer xenograft models, we show that pharmaceutical inhibition of TOPK potentiates the efficacy of fractionated irradiation. Furthermore, we provide in vitro evidence that TOPK plays a hitherto unknown role during S phase, showing that TOPK depletion increases fork stalling and collapse under conditions of replication stress and exogenous DNA damage. Transient knockdown of TOPK was shown to impair recovery from fork stalling and to increase the formation of replication-associated single-stranded DNA foci in H460 lung cancer cells. We also show that TOPK interacts directly with CHK1 and Cdc25c, two key players in the checkpoint signalling pathway activated after replication fork collapse. This study thus provides novel insights into the mechanism by which TOPK activity supports the survival of cancer cells, facilitating checkpoint signalling in response to replication stress and DNA damage.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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ISSN:1350-9047
1476-5403
1476-5403
DOI:10.1038/s41418-020-00655-1