Abstract Prostate cancer frequently acquires resistance to androgen receptor (AR)-targeted therapies through lineage plasticity, leading to neuroendocrine prostate cancer (NEPC), an aggressive and therapy-resistant subtype. BRN2 (POU3F2) is a key transcription factor that drives this transition and is normally repressed by AR signaling; however, the upstream mechanisms that activate BRN2 during therapy resistance remain poorly defined. We identify Polo-like kinase 1 (Plk1), a mitotic kinase upregulated in advanced disease, as a previously unrecognized upstream regulator of BRN2. Plk1 directly phosphorylates BRN2 at a conserved motif, enhancing its transcriptional activity and promoting downstream neuroendocrine reprogramming. Disruption of this phosphorylation markedly diminishes neuroendocrine marker expression and inhibits cellular plasticity. RNA-seq analysis further revealed suppression of EMT-associated transcriptional programs as a major downstream consequence of impaired BRN2 phosphorylation. In vivo, using a robust NEPC mouse model, inhibition of Plk1-dependent BRN2 activation reprograms tumor histology and molecular phenotype toward an AR-positive prostate adenocarcinoma (ARPC) state, indicating inhibition of lineage plasticity. These findings identify Plk1-mediated BRN2 phosphorylation as a critical driver of neuroendocrine transdifferentiation and highlight the Plk1-BRN2 axis as a promising therapeutic target to prevent NEPC progression in castration-resistant prostate cancer. Citation Format: Fatemeh Seilani, Meng Wu, Jia Peng, Mohammad Esfini Farahani, Xinyi Wang, Jinghui Liu, Yanquan Zhang, Ruixin Wang, Xiaoqi Liu. Plk1-BRN2 signaling axis drives lineage plasticity in castration-resistant prostate cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5965.
Seilani et al. (Fri,) studied this question.