The RAS/Raf1/MEK/ERK Signaling Pathway Facilitates VSV-mediated Oncolysis: Implication for the Defective Interferon Response in Cancer Cells

Abstract

Vesicular stomatitis virus (VSV) can replicate in malignant cells more efficiently than in normal cells. Although the selective replication appears to be caused by defects in the interferon (IFN) system in malignant cells, the mechanisms which render these cells less responsive to IFN remain poorly understood. Here we present evidence that an activated RAS/Raf1/MEK/ERK pathway plays a critical role in the defects. NIH 3T3 or human primary cells stably expressing active RAS or Raf1 were rapidly killed by VSV. Although IFNalpha treatment no longer protected the RAS- or Raf1-overexpressing cells from VSV infection, responsiveness to IFNalpha was restored following treatment with the mitogen-activated protein kinase kinase (MEK) inhibitor U0126. Similarly, human cancer-derived cell lines became more responsive to IFNalpha in conjunction with U0126 treatment. Intriguingly, dual treatment with both IFNalpha and U0126 severely reduced the levels of viral RNAs in the infected cells. Moreover, cancer cells showed defects in inducing an IFNalpha-responsive factor, MxA, which is known to block VSV RNA synthesis, and U0126 restored the MxA expression. Our observations suggest that activation of the extracellular signal-regulated protein kinase (ERK) signaling leads to the defect in IFNalpha-mediated upregulation of MxA protein, which facilitates VSV oncolysis. In view of the fact that 30% of all cancers have constitutive activation of the RAS/Raf1/MEK/ERK pathway, VSV would be an ideal oncolytic virus for targeting such cancers.

Attenuated, Oncolytic, but Not Wild-Type Measles Virus Infection Has Pleiotropic Effects on Human Neutrophil Function

“…First described in a pivotal study regarding VSV (35), several studies have since demonstrated that one mechanism of the selective tumor cytotoxicity of oncolytic viruses relates to deficiencies in the IFN-mediated antiviral responses of tumor rendering viral replication and killing more potent in tumor cells than in normal cells with an intact pathway. There is some evidence that an activated RAS/Raf1/ MEK/ERK pathway plays a critical role in the defects, at least as far as VSV-mediated lysis is concerned (36). Other viruses include Newcastle Disease Virus (37) and adenovirus (38).…”

Gene therapy progress and prospects cancer: oncolytic viruses

“…40,41 Similarly, viruses such as VSV showed preferential replication in cells with an activated Ras-ERK pathway and defective IFN pathways. 42 A vaccinia virus mutant with a deletion in B18R, whose gene product neutralizes type I IFNs, showed IFN-dependent cancer selectivity and efficacy. 31 It has also been shown that adenovirusinduced ERK activation is critical to viral replication.…”

Chemical targeting of the innate antiviral response by histone deacetylase inhibitors renders refractory cancers sensitive to viral oncolysis

“…To test this idea, in vitro cytotoxicity of PC3 cells was assessed at varying concentrations of VSV and HDI in a fixed ratio design. Combination indices (CI) (10) (32,33) (Fig. 3 A-C, and Fig.…”