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CCRK is a novel signalling hub exploitable in cancer immunotherapy

journal contribution
posted on 2023-06-09, 11:49 authored by Myth T Mok, Jingying Zhou, Wenshu Tang, Xuezhen Zeng, Antony OliverAntony Oliver, Simon E Ward, Alfred S L Cheng
Cyclin-dependent kinase 20 (CDK20), or more commonly referred to as cell cycle-related kinase (CCRK), is the latest member of CDK family with strong linkage to human cancers. Accumulating studies have reported the consistent overexpression of CCRK in cancers arising from brain, colon, liver, lung and ovary. Such aberrant up-regulation of CCRK is clinically significant as it correlates with tumor staging, shorter patient survival and poor prognosis. Intriguingly, the signalling molecules perturbed by CCRK are divergent and cancer-specific, including the cell cycle regulators CDK2, cyclin D1, cyclin E and RB in glioblastoma, ovarian carcinoma and colorectal cancer, and KEAP1-NRF2 cytoprotective pathway in lung cancer. In hepatocellular carcinoma (HCC), CCRK mediates virus-host interaction to promote hepatitis B virus-associated tumorigenesis. Further mechanistic analyses reveal that CCRK orchestrates a self-reinforcing circuitry comprising of AR, GSK3ß, ß-catenin, AKT, EZH2, and NF-?B signalling for transcriptional and epigenetic regulation of oncogenes and tumor suppressor genes. Notably, EZH2 and NF-?B in this circuit have been recently shown to induce IL-6 production to facilitate tumor immune evasion. Concordantly, in a hepatoma preclinical model, ablation of Ccrk disrupts the immunosuppressive tumor microenvironment and enhances the therapeutic efficacy of immune checkpoint blockade via potentiation of anti-tumor T cell responses. In this review, we summarized the multifaceted tumor-intrinsic and -extrinsic functions of CCRK, which represents a novel signalling hub exploitable in cancer immunotherapy.

Funding

Structural Biology of DNA Damage Response and Repair Mechanisms; G2176; CANCER RESEARCH UK; C302/A24386

History

Publication status

  • Published

Journal

Pharmacology and Therapeutics

ISSN

0163-7258

Publisher

Elsevier

Volume

186

Page range

138-151

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Research groups affiliated with

  • Genome Damage and Stability Centre Publications
  • Sussex Drug Discovery Centre Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2018-01-30

First Compliant Deposit (FCD) Date

2018-01-30

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