靶向調控 MCTP1–FYN–MEF2C 訊息軸抑制晚期攝護腺癌之神經內分泌分化與腫瘤進展

游家豪¹、溫玉清^1,2、劉晏年³

¹ 臺北市立萬芳醫院泌尿科-委託臺北醫學大學辦理

² 臺北醫學大學泌尿學科

³ 臺北醫學大學癌症生物學與藥物研發研究所

Therapeutic Targeting of the MCTP1–FYN–MEF2C Axis Suppresses Neuroendocrine Differentiation and Tumor Progression

in Advanced Prostate Cancer

Chia-Hao You¹, Yu-Ching Wen^1,2, Yen-Nien Liu³

¹ Department of Urology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

² Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

³ Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan

Purpose:

Neuroendocrine prostate cancer (NEPC) is a highly aggressive and therapy-refractory state that often emerges following prolonged androgen deprivation therapy (ADT). Understanding the molecular mechanisms driving lineage plasticity and resistance is critical to identify new therapeutic strategies. Multiple C2-domain and transmembrane-region protein 1 (MCTP1) has recently been implicated in epithelial-to-mesenchymal transition (EMT) and neuroendocrine differentiation (NED). This study explores the MCTP1–FYN–MEF2C signaling axis as a potential therapeutic target in castration-resistant and neuroendocrine prostate cancer (CRPC/NEPC).

Materials and Methods:

Transcriptomic and proteomic analyses were performed in prostate cancer tissues and cell-line models to identify MCTP1-regulated pathways. Functional assays, calcium flux imaging, and chromatin immunoprecipitation were used to examine the MCTP1–FYN–MEF2C interaction. A structure-guided virtual screening was conducted to identify small-molecule inhibitors targeting MCTP1's C2 domains. The therapeutic efficacy of the lead compound (NCI 402433) was validated in enzalutamide-resistant and small-cell prostate cancer xenograft models.

Results:

ADT significantly increased MCTP1 expression, enhancing FYN activation and calcium-dependent MEF2C signaling. This MCTP1/FYN/MEF2C feedback loop promoted EMT, NED, and osteogenic gene expression (e.g., ALPL), leading to bone-invasive and therapy-resistant phenotypes. Pharmacologic inhibition of MCTP1 disrupted calcium flux, downregulated NE markers (CHGA, SYP, ENO2), and suppressed tumor growth in CRPC and NEPC models without systemic toxicity.

Conclusion:

MCTP1 acts as a calcium-responsive oncogenic driver that coordinates FYN–MEF2C signaling to promote neuroendocrine differentiation and resistance in advanced prostate cancer. Identification of a first-in-class MCTP1 inhibitor establishes this axis as a druggable therapeutic target, offering a promising strategy to overcome treatment resistance in castration-resistant and neuroendocrine prostate cancer.