title: Novel biomarkers of resistance of pancreatic cancer cells to oncolytic vesicular stomatitis virus.
abstract: 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.
authors.affiliation: Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Hastie
authors.affiliation: Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC, USA.
authors.forename: Marcela
authors.initials: M
authors.lastname: Cataldi
authors.affiliation: Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC, USA.
authors.forename: Megan J
authors.initials: MJ
authors.lastname: Moerdyk-Schauwecker
authors.affiliation: Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC, USA.
authors.forename: Sébastien A
authors.initials: SA
authors.lastname: Felt
authors.affiliation: Cannon Research Center, Carolinas Healthcare System, Charlotte, NC, USA.
authors.forename: Nury
authors.initials: N
authors.lastname: Steuerwald
authors.affiliation: Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC, USA.
authors.forename: Valery Z
authors.initials: VZ
authors.lastname: Grdzelishvili
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000577:Amides / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor / Q000378:metabolism*; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000628:therapy*; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D015536:Down-Regulation; D019204:GTP-Binding Proteins / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors; D007370:Interferon Type I / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors; D009154:Mutation; D064547:Myxovirus Resistance Proteins / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D009570:Nitriles; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000628:therapy*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology; D059467:Transcriptome / Q000187:drug effects; D018116:Vesiculovirus / Q000502:physiology*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000577:Amides; D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; C459199:EPSTI1 protein, human; C490287:GBP1 protein, human; D007370:Interferon Type I; D047908:Intracellular Signaling Peptides and Proteins; C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D009363:Neoplasm Proteins; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D034741:RNA, Small Interfering; D013876:Thiophenes; C417551:XAF1 protein, human; C540383:ruxolitinib; C499326:2-((aminocarbonyl)amino)-5-(4-fluorophenyl)-3-thiophenecarboxamide; C507904:JAK1 protein, human; C507924:JAK2 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D051550:I-kappa B Kinase; D019204:GTP-Binding Proteins
keywords: biomarker of resistance; interferon-stimulated gene; oncolytic virus; pancreatic cancer; vesicular stomatitis virus