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Citron kinase (CIT) drives prostate cancer growth and treatment resistance by regulating cell division. Inhibiting CIT kinase activity shows therapeutic potential against aggressive and resistant prostate cancers.

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Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Prostate cancer is a leading cause of cancer death in men.
  • Understanding prostate cancer cell division mechanisms is crucial for overcoming treatment resistance.
  • Citron kinase (CIT) is a mitotic AGC family protein kinase implicated in cell cycle regulation.

Purpose of the Study:

  • To investigate the role of citron kinase (CIT) in prostate cancer growth and progression.
  • To determine if CIT kinase activity is a potential therapeutic target for prostate cancer.
  • To identify CIT substrates and their role in aggressive and treatment-resistant prostate cancer.

Main Methods:

  • Analysis of CIT expression in prostate cancer tissues and cell lines.
  • Investigating the effect of CIT silencing on prostate cancer cell and xenograft growth.
  • Evaluating the efficacy of a CIT kinase inhibitor (OTS-167) in preclinical models.
  • Identifying CIT substrates using in vivo methods.

Main Results:

  • CIT is overexpressed in prostate cancer and correlates with tumor growth and aggressive progression.
  • CIT overexpression is regulated by an E2F2-Skp2-p27 signaling axis and confers resistance to androgen deprivation therapy.
  • CIT silencing inhibits prostate cancer growth without affecting normal cells, suggesting a therapeutic window.
  • The multikinase inhibitor OTS-167 potently inhibits CIT kinase activity and reduces proliferation of treatment-resistant prostate cancer cells and organoids.
  • CIT regulates diverse cellular functions, including proliferation and alternative splicing, which are enriched in treatment-resistant tumors.

Conclusions:

  • Citron kinase (CIT) is a pivotal, druggable driver of prostate cancer progression and treatment resistance.
  • Targeting CIT kinase activity with inhibitors like OTS-167 offers a promising therapeutic strategy for aggressive and resistant prostate cancers.
  • CIT's diverse substrate regulation highlights its central role in the hallmarks of aggressive prostate cancer.