Abstract Neuroendocrine prostate cancer (NEPC) is a deadly disease with limited treatment options, a predicted increase in incidence, and poor response to conventional therapeutics. NEPC is characterized by muscle-invasive disease and frequent rates of distant metastasis1. There is no FDA-approved molecular targeted treatment for NEPC, and the lack of therapeutics is reflected in the overall survival rate, which remains around 9 months1-2. We have previously reported that PVT1 exon 9 overexpression induces the development of in vivo tumors with the NEPC phenotype, and inhibition of PVT1 exon 9 is an effective therapeutic target in these tumors. Understanding the underlying molecular mechanisms that drive aggressive prostate cancer subtypes is desperately needed. Here, we report findings from the characterization of the novel PVT1 exon 9 overexpressing NEPC subtype. PVT1 exon 9 transcript is found within both the nuclear and cytosolic compartments. Upregulation of PVT1 exon 9 leads to the overexpression of the innate immune surveillance proteins RSAD2 and CMPK2. In PVT1 exon 9 overexpressing NEPC, RSAD2 is localized mainly to the nucleus, a novel observation, via an interaction between the nuclear import complex KPNB1/KPNA2 and its newly identified nuclear localization sequence. We have observed a significantly enhanced expression of the nuclear import complex proteins as well as a direct interaction with PVT1 exon 9 and KPNB1. The function of the RSAD2 nuclear localization is unclear, but PVT1 exon 9 mediated-RSAD2 overexpression does lead to increased interferon gamma secretion. PVT1 exon 9 directly binds to RSAD2 protein as well as the CMPK2 protein. We have observed that CMPK2 overexpression is caused by the overexpression of RSAD2. CMPK2 is localized within the nucleus and cytosolic compartments. Both RSAD2 and CMPK2 proteins do not directly interact, but the RSAD2 protein does bind to the CMPK2 transcript within the nucleus, leading to changes in CMPK2 RNA stability. CMPK2 overexpression is not involved in mediating interferon gamma signaling and is downstream of this signaling network. PVT1 exon 9 overexpression leads to androgen receptor (AR) suppression via an unknown mechanism independent of RSAD2 or CMPK2 activity. Targeting PVT1 exon 9 with antisense oligonucleotides at its 5’ end leads to loss of PVT1 exon 9 expression, decoupling of PVT1 exon 9 from RSAD2 and CMPK2 proteins, re-expression of AR, and loss of cell viability, migration, invasion, and colony formation. Co-treatment with PVT1 exon 9 antisense oligonucleotides and the AR inhibitor enzalutamide leads to significant inhibition of NEPC cell proliferation/viability, invasion and migration. This novel signaling mechanism present in a subset of neuroendocrine prostate cancer is a clinically relevant and targetable molecular aberration. Further investigation is warranted to understand the best treatment strategy for this subtype, as well as identify other aggressive prostate cancer subtypes that may benefit from PVT1 exon 9 inhibition. Citation Format: Rachel E. Bonacci, Seidu Adams, Chinedum C. Udekwu, Siti Khaula Nurazizah, Luke Washington, Olorunseun O. Ogunwobi. RSAD2-CMPK2 signaling mediates PVT1 exon 9 action in an AR-independent manner in PVT1 exon 9 overexpressing neuroendocrine prostate cancers 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 B005.
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