A MYC Family Switch: L-MYC Drives and Maintains Neuroendocrine Lineage Programs in Prostate Cancer

ABSTRACT Neuroendocrine prostate cancer (NEPC) is an aggressive, therapy-resistant subtype that emerges through lineage plasticity following androgen receptor (AR) pathway inhibition. Although MYC family oncogenes are central to prostate cancer progression, the role of MYCL (L-MYC) in NEPC has remained unclear. Here, we show that MYCL is selectively and robustly upregulated in NEPC patient samples and cell line models, whereas MYC is downregulated and MYCN remains low, revealing a lineage-associated MYC family switch. MYCL expression strongly correlates with the neuroendocrine lineage regulators ASCL1 and INSM1 and inversely with adenocarcinoma-associated genes. Mechanistically, MYCL activation is not driven by genomic amplification but reflects a permissive epigenetic landscape. Functionally, MYCL overexpression suppresses AR signaling and induces neuroendocrine-like transcriptional reprogramming, whereas MYCL knockdown disrupts neuroendocrine lineage identity and restores adenocarcinoma-associated gene expression, including MYC. We further identify ASCL1 and INSM1 as upstream regulators of MYCL, establishing a conserved neuroendocrine transcriptional axis. Together, these findings define MYCL as a lineage-specific regulator that drives neuroendocrine identity and plasticity in advanced prostate cancer.