*4.5. Newcastle Disease Virus (NDV)*

NDV is an avian paramyxovirus with a negative-sense, single-stranded RNA enclosed in its viral envelope. It was thought that some NDV strains have oncolytic properties by taking advantage of the inability of the tumor cells to elicit an anti-viral response due to deficiencies in IFN pathway [14]. Therefore, the search for markers of resistance to NDV-mediated oncolysis have focused on the antiviral pathways.

Krishnamurthy et al. showed that NDV susceptibility was linked to impairment of the type I interferon pathway [126]. Fibrosarcoma cells that were susceptible to NDV infection were unable to induce IFN-β production [126]. Specifically, the STAT1 and STAT2 phosphorylation was significantly reduced in the permissive tumor cells, resulting in reduced expression of ISG mRNAs and IFN-β [126]. In an approach to overcome resistance, Zamarin et al. engineered an NDV variant expressing an IFNα-antagonist, which demonstrated enhanced oncolytic activity in melanoma cell lines compared to the NDV strain without the IFN-antagonist [127].

In contrast with these findings, Mansour et al. revealed that the human non-small-cell lung cancer cell line A549 was susceptible to NDV oncolysis, despite the production of high levels of type I IFN response. It was proposed that the restriction mechanism in NDV oncolysis was based on the expression level of the anti-apoptotic protein Bcl-xl, where over-expression of Bcl-xl correlates with increased sensitivity to NDV [128]. Moreover, it was recently demonstrated that STAT3 inhibition suppresses immunogenic cell death (ICD) by NDV in melanoma tumor cells [129]. Interestingly, Bcl-xl is one of the target genes of active STAT3 [129].

Another potential marker for NDV cytotoxicity is the status of the autophagy pathway. Meng et al. showed in U251 glioma cells that NDV exploits the autophagic machinery to increase its replication. In this study, inhibition of BECLIN-1 or ATG5 gene, which are critical for the autophagosome formation, led to reduced production of NDV [130]. A more recent study showed autophagy modulators act as sensitizers for NDV in drug-resistant lung cancers [131]. On a different note, Puhlmann et al. showed that the oncogenic protein, Rac 1, is essential for NDV replication and it could confer sensitivity to viral replication [132]. Rac1 is a Rho GTPase protein and is involved in processes like cell proliferation and cytoskeleton organization [133]. In GBM, it has been shown that Rac1 is important for maintaining the stemness of GSCs, which may suggest that NDV could potentially be utilized to target the treatment-resistant cancer stem cell clones within GBM [134].
