2-((aminocarbonyl)amino)-5-(4-fluorophenyl)-3-thiophenecarboxamide and Carcinoma--Pancreatic-Ductal

Vesicular stomatitis virus (VSV) based recombinant viruses (such as VSV-ΔM51) are effective oncolytic viruses (OVs) against a majority of pancreatic ductal adenocarcinoma (PDAC) cell lines. However, some PDAC cell lines are highly resistant to VSV-ΔM51. We recently showed that treatment of VSV-resistant PDAC cells with ruxolitinib (JAK1/2 inhibitor) or TPCA-1 (IKK-β inhibitor) breaks their resistance to VSV-ΔM51. Here we compared the global effect of ruxolitinib or TPCA-1 treatment on cellular gene expression in PDAC cell lines highly resistant to VSV-ΔM51. Our study identified a distinct subset of 22 interferon-stimulated genes (ISGs) downregulated by both ruxolitinib and TPCA-1. Further RNA and protein analyses demonstrated that 4 of these genes (MX1, EPSTI1, XAF1, and GBP1) are constitutively co-expressed in VSV-resistant, but not in VSV-permissive PDACs, thus serving as potential biomarkers to predict OV therapy success. Moreover, shRNA-mediated knockdown of one of such ISG, MX1, showed a positive effect on VSV-ΔM51 replication in resistant PDAC cells, suggesting that at least some of the identified ISGs contribute to resistance of PDACs to VSV-ΔM51. As certain oncogene and tumor suppressor gene variants are often associated with increased tropism of OVs to cancer cells, we also analyzed genomic DNA in a set of PDAC cell lines for frequently occurring cancer associated mutations. While no clear correlation was found between such mutations and resistance of PDACs to VSV-ΔM51, the analysis generated valuable genotypic data for future studies.

Topics: Adaptor Proteins, Signal Transducing; Amides; Apoptosis Regulatory Proteins; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; DNA Mutational Analysis; Down-Regulation; Gene Expression; Gene Expression Profiling; GTP-Binding Proteins; Humans; I-kappa B Kinase; Interferon Type I; Intracellular Signaling Peptides and Proteins; Janus Kinase 1; Janus Kinase 2; Mutation; Myxovirus Resistance Proteins; Neoplasm Proteins; Nitriles; Oncolytic Virotherapy; Oncolytic Viruses; Pancreatic Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; RNA Interference; RNA, Small Interfering; Thiophenes; Transcriptome; Vesiculovirus; Virus Replication