Abstract 5624: The antiviral, Daclatasvir, disrupts ASCL1-EZH2 signaling and impairs survival of neuroendocrine prostate cancer cells

Abstract Management of neuroendocrine prostate cancer (NEPC) is extremely difficult not only because available therapeutic regimens cannot effectively kill NEPC cells but also due to the aggressive, highly metastatic nature of NEPC cells to invade distant organs. Development of effective therapeutic agents for NEPC is urgently needed but is suffering from lack of proper understanding about critical and selective molecular targets. Recent molecular analyses revealed that the pseudokinase, Tribbles 2 (TRIB2), is consistently overexpressed both in the treatment emergent as well as de novo NEPC cells and tumors and plays a critical role in the survival and maintenance of neuroendocrine characteristics in NEPC cells. Daclatasvir (DCV), an FDA-approved antiviral agent, was found to directly bind and destabilize TRIB2 protein and prime it for degradation via activation of proteasomes. However, the extent to which DCV impacts the viability and lineage characteristics in NEPC cells remain unclear. We report here that DCV inhibits the growth and survival of NEPC cells by inducing caspase-mediated apoptosis. Mechanistically, DCV disrupts the TRIB2 downstream signal transduction cascade which involves the proneuronal transcription factor, Achaete-scute homolog 1 (ASCL1) and the epigenetic regulator, Enhancer of zeste homolog 2 (EZH2). Interestingly, inhibition of the ASCL1-EZH2 signaling axis by DCV showed an increase in the protein level of the androgen receptor (AR). Moreover, we found that DCV at lower, sub-lethal doses synergize with AR inhibitors, such as enzalutamide, to enhance NEPC cell death, suggesting improved efficacy of these two classes of anticancer agents in combination. Since DCV is well-tolerated in humans, and is approved for treatment of viral hepatitis, our findings position DCV as a promising therapeutic agent for NEPC, a highly aggressive, drug-resistant subtype of prostate cancer with extremely limited therapeutic options. Citation Format: Rohith Guddeti, Jitender Monga, Craig Rogers, Dhananjay Chitale, Shirish Gadgeel, Jagadananda Ghosh. The antiviral, Daclatasvir, disrupts ASCL1-EZH2 signaling and impairs survival of neuroendocrine prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5624.