TLK1>Nek1 Axis Promotes Nuclear Retention and Activation of YAP with Implications for Castration-Resistant Prostate...

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Prostate cancer (PCa) progression to castration-resistant PCa (CRPC) remains a significant clinical challenge, necessitating a deeper understanding of underlying mechanisms.
• The Hippo pathway, particularly the co-activator YAP, plays a crucial role in CRPC by enabling androgen receptor (AR) signaling even at low testosterone levels.
• Recent findings implicate the TLK1>NEK1 axis in the post-transcriptional activation of YAP through phosphorylation at Y407.

Purpose of the Study:

• To elucidate the functional significance of YAP phosphorylation at Y407 in CRPC.
• To investigate the therapeutic potential of inhibiting the TLK1>NEK1 axis using J54 (TLK1 inhibitor) in preclinical models of prostate cancer.

Main Methods:

• Investigated the effect of J54 on YAP phosphorylation, nuclear retention, and degradation in prostate cancer cells.
• Utilized chromatin immunoprecipitation (ChIP) to assess YAP binding to target gene promoters.
• Evaluated the efficacy of combined ARSI and J54 treatment in LNCaP and VCaP xenograft models.

Main Results:

• J54 treatment reversed YAP phosphorylation at Y407, reduced nuclear YAP, and promoted cytoplasmic YAP degradation, counteracting Enzalutamide-induced YAP accumulation.
• Phosphorylated YAP (pYAP-Y407) enhances association with AR and TEAD1, promoting transcription of YAP/AR target genes; J54 disrupts this interaction.
• Combination therapy with ARSI and J54 induced tumor regression in LNCaP xenografts, but VCaP tumors recurred, suggesting alternative CRPC pathways despite YAP suppression.

Conclusions:

• YAP phosphorylation at Y407 is critical for nuclear retention and co-activation of AR/TEAD1 target genes in prostate cancer.
• Inhibition of the TLK1>NEK1 axis via J54 represents a promising strategy to overcome AR signaling in CRPC, particularly in models sensitive to this pathway.
• The recurrence of VCaP tumors highlights the complexity of CRPC and the potential for alternative signaling pathways that may require combination therapies beyond targeting YAP.