Novel biomarkers of resistance of pancreatic cancer cells to oncolytic vesicular stomatitis virus

// Eric Hastie 1, * , Marcela Cataldi 1, * , Megan J. Moerdyk-Schauwecker 1, * , Sebastien A. Felt 1, * , Nury Steuerwald 2 , Valery Z. Grdzelishvili 1 1 Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC, USA 2 Cannon Research Center, Carolinas Healthcare System, Charlotte, NC, USA * These authors have contributed equally to this work Correspondence to: Valery Z. Grdzelishvili, email: vzgrdzel@uncc.edu Keywords: pancreatic cancer, oncolytic virus, vesicular stomatitis virus, interferon-stimulated gene, biomarker of resistance Received: March 13, 2016     Accepted: July 27, 2016     Published: August 11, 2016 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.