Inhibition of Janus Kinase 1 synergizes docetaxel sensitivity in prostate cancer cells

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Prostate cancer (PCa) is a leading cause of cancer mortality in men globally.
• Docetaxel is a first-line treatment for metastatic castration-resistant PCa, but dose-limiting toxicities often necessitate dose reductions.
• Improving docetaxel efficacy and reducing its toxicity remain critical challenges in PCa treatment.

Purpose of the Study:

• To identify novel therapeutic targets that can enhance docetaxel sensitivity in prostate cancer cells.
• To investigate the potential of targeting Janus kinase 1 (JAK1) in combination with docetaxel for PCa treatment.

Main Methods:

• A high-throughput kinome-wide loss-of-function screen was employed to identify genes whose inhibition enhances docetaxel sensitivity.
• Drug-gene interaction analyses were performed to identify druggable targets.
• The effects of JAK1 inhibition (using baricitinib, ruxolitinib) and JAK2 inhibition (using fedratinib) on docetaxel sensitivity were evaluated in different PCa cell lines (DU145, PC3, LNCaP).

Main Results:

• Fifteen lethality hits were identified, with Janus kinase 1 (JAK1) emerging as a viable target.
• Depletion of endogenous JAK1 enhanced docetaxel-induced apoptosis in PCa cells.
• Inhibition of JAK1/2 by baricitinib and ruxolitinib synergized with docetaxel in AR-negative PCa cells (DU145, PC3), but not in AR-positive LNCaP cells. JAK2-specific inhibition showed no synergistic effect, indicating JAK1 is the primary mediator.

Conclusions:

• Targeting JAK1 in combination with docetaxel represents a promising therapeutic strategy for prostate cancer.
• This combination therapy may be particularly effective in androgen receptor-negative PCa.
• Further investigation into JAK1 inhibitors alongside docetaxel could lead to improved treatment outcomes for PCa patients.