*5.3. Resistance to Virus-Mediated Apoptosis*

Inhibition of apoptosis is a hallmark of many malignancies, including PDAC [187], and PDAC with decreased expression or activation of certain apoptotic proteins have the potential to limit/delay cell death following VSV infection [166,188–190]. Our study demonstrated that all three tested VSV recombinants (VSV-GFP (WT M gene), VSV-p1-GFP (WT M gene, GFP in the first position in the genome), and VSV-∆M51-GFP) induced caspase 3 cleavage following infection, but VSV-∆M51-GFP induced more caspase 3 cleavage in all cell lines with VSV-inducible Type I IFN responses, despite similar replication levels for the viruses [59]. This indicates a positive role for the ∆M51 mutation, and therefore host antiviral responses, in apoptosis induction, and is unlikely to be simply a result of virus attenuation as VSV-p1-GFP induced caspase cleavage similarly to VSV-GFP. Further, VSV- ∆M51-GFP induces both the extrinsic and intrinsic apoptosis pathways in most PDACs, however, we observed inhibition of VSV-induced and drug-induced apoptosis in some PDAC cells lines, and that was observed even when VSV replication was stimulated using JAK1 inhibitors [59]. In general, our study has demonstrated that resistance of some PDAC cell lines to VSV-mediated oncolysis could be not only due to type I IFN responses that limit virus replication, but also to cellular defects in apoptosis.
