Oncolytic virus (OV) therapy is an anticancer therapy using replication-competent viruses selectively infecting, replicating in and killing cancer cells. Human pancreatic ductal adenocarcinoma (PDAC) cell lines are highly heterogeneous in their permissiveness to oncolytic vesicular stomatitis virus (VSV), in part due to differences in antiviral interferon (IFN) signaling. VSV-resistant PDACs were shown to constitutively express high levels of several IFN-stimulated genes (ISGs). This work identified two additional defects in VSV-resistant PDACs, apoptosis (Chapter 2) and cell attachment (Chapter 3). In Chapter 2, we discovered that three cell lines constitutively expressing high levels of several ISGs were also resistant to VSV-mediated apoptosis under most experimental conditions, even when VSV replication was improved by JAK Inhibitor I treatment. Two of these cell lines also poorly activated apoptosis when treated with Fas activating antibody, suggesting a general defect in apoptosis. In Chapter 3, we showed a dramatically weaker attachment of VSV in the most resistant PDAC cell line, HPAF-II. Although sequence analysis of the VSV receptor, low density lipoprotein receptor (LDLR), did not reveal any amino acid substitutions, HPAF-II cells displayed the lowest level of LDLR expression and LDLR activity. Treatment of cells with statins (HMG-CoA reductase inhibitors) strongly increased LDLR expression levels, but did not improve VSV attachment. However, LDLR-independent attachment of VSV to HPAF-II cells was dramatically improved by treating cells with polycations like polybrene or DEAE-dextran. Moreover, we successfully used a novel triple combination treatment to break the resistance of HPAF-II in vitro to VSV by combining VSV with polybrene or DEAE-dextran and ruxolitinib (JAK 1/2 inhibitor), thus simultaneously improving VSV attachment and replication.