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Targeting TOPK sensitises tumour cells to radiation-induced damage by enhancing replication stress
Katharine J Herbert1, Rathi Puliyadi1, Remko Prevo1
1MRC Oxford Institute for Radiation Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK.
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.
Insights
T-LAK-originated protein kinase (TOPK) is overexpressed in cancers and is a promising target for new therapeutics. Inhibiting TOPK enhances radiation treatment efficacy for solid tumors by impacting DNA replication and repair pathways.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- T-LAK-originated protein kinase (TOPK) is overexpressed in various cancers but not in normal tissues, making it a potential therapeutic target.
- TOPK-targeting agents are under development, showing promise for targeted cancer therapies.
Purpose of the Study:
- To investigate the efficacy of a TOPK inhibitor (OTS964) in combination with radiation therapy for solid tumors.
- To elucidate the role of TOPK in DNA replication, repair, and checkpoint signaling in cancer cells.
Main Methods:
- Utilized lung cancer xenograft models (H460 and Calu-6) to assess the combined effects of TOPK inhibition and fractionated irradiation.
- Performed in vitro experiments involving TOPK depletion to analyze its impact on replication fork dynamics under stress.
- Investigated the interaction of TOPK with key checkpoint proteins like CHK1 and Cdc25c.
Main Results:
- TOPK inhibition with OTS964 potentiated the efficacy of fractionated irradiation in lung cancer xenografts.
- TOPK depletion led to increased replication fork stalling and collapse under replication stress and DNA damage.
- TOPK knockdown impaired recovery from fork stalling and increased single-stranded DNA foci formation.
- TOPK was found to directly interact with CHK1 and Cdc25c, crucial for checkpoint signaling.
Conclusions:
- TOPK is a validated therapeutic target for solid tumors, particularly when combined with radiation therapy.
- TOPK plays a critical role in maintaining cancer cell survival by facilitating checkpoint signaling during replication stress and DNA damage.
- This study reveals a novel mechanism of TOPK action in DNA damage response, offering new avenues for cancer treatment strategies.
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