Abstract Lineage plasticity and transition from prostate adenocarcinoma (PRAD) to neuroendocrine prostate cancer (NEPC) is an increasingly common mechanism of resistance to androgen receptor (AR) inhibition in castration-resistant prostate cancer. Transition to NEPC is associated with loss of AR expression, activation of neuroendocrine transcriptional programs, and an aggressive phenotype with poor outcomes. Currently, the mechanisms underlying this lineage transition remain unclear, which has hindered drug discovery efforts. Nearly all NEPC tumors exhibit dual loss of p53 and Rb, however, this is insufficient to drive lineage transition from PRAD to NEPC. Using patient samples, patient cohorts and patient-derived xenograft models, we identified the transcription factor MYCL as highly expressed in a subset of NEPC tumors, with little expression in PRAD. MYCL is an essential gene in preclinical MYCL+ NEPC models, and expression of MYCL in PRAD models is sufficient to downregulate AR expression and induce complete resistance to AR inhibition only in the context of dual p53/Rb loss of function. In contrast, expression of the other Myc family members MYC and MYCN do not regulate AR expression and result in partial resistance to AR inhibition regardless of p53/Rb status. RNA-sequencing in p53/Rb-null models indicated that MYC and MYCN regulate similar transcriptional programs, corresponding primarily with the interferon and inflammatory responses. However, MYCL expression promotes a unique transcriptional program associated with neuroendocrine and neuronal development gene sets and strongly represses the AR transcriptional program. Similarly, ATAC-sequencing of p53/Rb-null models expressing MYC, MYCN, or MYCL indicates that while all three MYC family members regulate chromatin accessibility at a common core set of genomic sites, each MYC family member also regulates chromatin accessibility at unique sites. Concordant with RNA-sequencing results, MYCL unique sites correspond with neuronal and neuroendocrine gene sets. MYCL expression also results in decreased accessibility of the AR distal enhancer, providing a mechanistic basis for the decreased AR expression and repressed AR transcriptional program observed upon MYCL expression. In accordance with this data, we also find that MYCL expression induces morphological changes consistent with transition to a small-cell neuroendocrine phenotype. Using publicly available RNA interference and CRISPR screen data, we also find that models that express MYCL are differentially dependent upon Myc interacting proteins such as MNT and MAX. Ongoing work is focused on identifying the interactome and unique genetic dependencies of MYC, MYCN, and MYCL to gain a better understanding of the divergent functions and unique co-dependencies of each Myc family member. Collectively, this work implicates MYCL as a novel driver of lineage plasticity and provides insights into the unique and convergent functions of the three Myc family members in castration-resistant prostate cancer. Citation Format: Nicole A. Traphagen, Alok K. Tewari, Esmé Wheeler, Christian Alfieri, Sajin Patel, Rong Li, Michael Nyquist, Arnab Bose, Michael Haffner, Peter S. Nelson, Henry Long, Himisha Beltran, Myles Brown. MYCL drives lineage plasticity and resistance to androgen receptor inhibition in castration-resistant prostate cancer abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86 (2Suppl): Abstract nr B078.
Traphagen et al. (Tue,) studied this question.