NUAK2 is a therapeutically tractable regulator of RNA splicing and tumor progression in neuroendocrine prostate cancer.

Prostate cancer (PC) remains the second leading cause of cancer-related mortality in men. The emergence of treatment-emergent neuroendocrine prostate cancer (NEPC) arising from androgen receptor (AR) pathway inhibition poses a significant clinical challenge. Here, we report that NUAK family kinase 2 (NUAK2) is an actionable therapeutic target in NEPC. NUAK2 expression is markedly elevated in NEPC patient specimens and preclinical models, and its genetic or pharmacologic inhibition suppresses NEPC tumor growth. The FDA-approved CDK4/6 inhibitor trilaciclib exerts potent inhibition of NUAK2, leading to marked tumor suppression alone and enhanced efficacy in combination with carboplatin. Integrated phosphor-target and interactome analyses demonstrate that NUAK2 engages core spliceosome components to regulate pre-mRNA splicing. As proof of principle, we validated that NUAK2 inhibition perturbs pre-mRNA splicing of EZH2 and TTK leading to reduced translation. Collectively, these findings establish NUAK2 as a clinically actionable regulator of RNA splicing and tumor progression in NEPC, revealing a novel mechanism by which trilaciclib exerts antitumor activity in NEPC.