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

Herbert, K. J. , Puliyadi, R., Prevo, R., Rodriguez-Berriguete, G., Ryan, A., Ramadan, K. and Higgins, G. S. (2021) Targeting TOPK sensitises tumour cells to radiation-induced damage by enhancing replication stress. Cell Death and Differentiation, 28(4), pp. 1333-1346. (doi: 10.1038/s41418-020-00655-1) (PMID:33168956) (PMCID:PMC8027845)

Abstract

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.

• Item Type: Articles
• Additional Information: Acknowledgements: We thank Rhodri Wilson for technical assistance. The Cancer Research UK/MRC Oxford Institute for Radiation Oncology is supported by core grants from the Medical Research Council and Cancer Research UK. GSH has been supported by Cancer Research UK Clinician Scientist Awards (grant numbers C34326/A13092 and C34326/A19590). OTS964 was kindly provided by OncoTherapy Science, Inc.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Herbert, Dr Katharine
• Authors: Herbert, K. J., Puliyadi, R., Prevo, R., Rodriguez-Berriguete, G., Ryan, A., Ramadan, K., and Higgins, G. S.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cell Death and Differentiation
• Publisher: Nature Publishing Group
• ISSN: 1350-9047
• ISSN (Online): 1476-5403
• Published Online: 09 November 2020
• Copyright Holders: Copyright © The Author(s) 2020
• First Published: First published in Cell Death and Differentiation 28(4): 1333-1346
• Publisher Policy: Reproduced under a Creative Commons licence