Citron Kinase Is a Druggable Target in Treatment-Resistant Prostate Cancer.

Prolonged treatment with androgen deprivation therapy (ADT) inevitably leads to castration-resistant prostate cancer (CRPC). Development of novel androgen-targeting agents and chemo/radiotherapies has resulted in improved survival. However, metastatic CRPC remains incurable. New therapeutics are greatly needed, and exploration of novel pathways such as the mechanisms underlying prostate cancer cell proliferation could potentially augment the natural course of CRPC. In the latest issue of Cancer Research, Rawat and colleagues delved deeply into the mechanistic role of citron kinase (CIT) in orchestrating prostate cancer proliferation and revealed its catalytic activity as a druggable target for treatment-resistant prostate cancer. The researchers utilized in vitro and in vivo methodologies to elucidate the function of CIT in mediating uncontrolled interphase progression and prostate cancer growth. Furthermore, the authors employed both androgen receptor-dependent and independent models to validate the significance of CIT kinase activity as a crucial factor in driving treatment-resistant prostate cancer growth. At a mechanistic level they determined that the E2F2-Skp2-p27 axis regulates CIT expression. Finally, they defined the landscape of CIT substrates in prostate cancer that encompasses a spectrum of cellular functions that spans key proliferation regulators to alternative splicing events. This comprehensive work provides insights into CIT as a potential biomarker for prostate cancer treatment resistance and disease progression and establishes the CIT kinase domain as a druggable target in CRPC. See related article by Rawat et al., p. 4142.