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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Vydané v:	Cell death and differentiation Ročník 28; číslo 4; s. 1333 - 1346
Hlavní autori:	Herbert, Katharine J, Puliyadi, Rathi, Prevo, Remko, Rodriguez-Berriguete, Gonzalo, Ryan, Anderson, Ramadan, Kristijan, Higgins, Geoff S
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	England Nature Publishing Group 01.04.2021
Predmet:	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
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Shrnutí:	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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1350-9047 1476-5403 1476-5403
DOI:	10.1038/s41418-020-00655-1