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bioRxiv · 10.64898/2026.06.24.734137

Multi-omics Profiling Reveals an NF-κB-Driven Anti-apoptotic Network Underlying Resistance to Oncolytic VSV in Prostate Cancer Cells

Abdelmageed, A.·Dewhurst, S.·Ferran, M.
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Abstract

The therapeutic efficacy of oncolytic viruses is often limited by the presence of tumor cells that resist virus-mediated killing. Here, we investigated the molecular mechanisms underlying resistance to Vesicular Stomatitis Virus (VSV) in PC3 cells, an aggressive metastatic prostate cancer (PrCa) cell line, using the VSV-sensitive LNCaP cell line as a comparator. RNA sequencing revealed that, relative to untreated cells, VSV-infected PC3 cells upregulated both pro-apoptotic genes, including BIM, PUMA, and NOXA, and anti-apoptotic and antiviral genes, including A20 and RIG-I. In addition, genes associated with antiviral and pro-survival pathways, including NF{kappa}B and PI3K-Akt signaling, were more highly expressed in PC3 cells than in LNCaP cells. At baseline, PC3 cells also exhibited elevated expression of multiple pro-survival genes, including BCL-xL, MCL1, and CK2, compared with LNCaP cells. Complementary proteomic analyses identified enhanced activation of NF{kappa}B, PI3K-Akt, and MSK1 signaling in VSV-infected PC3 cells relative to infected LNCaP cells. Furthermore, pharmacological inhibition of BCL-2 family proteins or NF{kappa}B signaling restored sensitivity to VSV-induced cell death in PC3 cells. Collectively, these findings identify NF{kappa}B-centered pro-survival signaling networks as key contributors to the resistant phenotype of PC3 cells and suggest that combining oncolytic virotherapy with targeted inhibitors may improve therapeutic efficacy in resistant prostate cancers.

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Abdelmageed, A., Dewhurst, S., Ferran, M.. 2026-06-25. Multi-omics Profiling Reveals an NF-κB-Driven Anti-apoptotic Network Underlying Resistance to Oncolytic VSV in Prostate Cancer Cells. https://doi.org/10.64898/2026.06.24.734137

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