Activated Ras Signaling Pathways and Reovirus Oncolysis: An Update on the Mechanism of Preferential Reovirus Replication in Cancer Cells

Abstract

The development of wild-type, unmodified Type 3 Dearing strain reovirus as an anticancer agent has currently expanded to 32 clinical trials (both completed and ongoing) involving reovirus in the treatment of cancer. It has been more than 30 years since the potential of reovirus as an anticancer agent was first identified in studies that demonstrated the preferential replication of reovirus in transformed cell lines but not in normal cells. Later investigations have revealed the involvement of activated Ras signaling pathways (both upstream and downstream) and key steps of the reovirus infectious cycle in promoting preferential replication in cancer cells with reovirus-induced cancer cell death occurring through necrotic, apoptotic, and autophagic pathways. There is increasing evidence that reovirus-induced antitumor immunity involving both innate and adaptive responses also contributes to therapeutic efficacy though this discussion is beyond the scope of this article. Here, we review our current understanding of the mechanism of oncolysis contributing to the broad anticancer activity of reovirus. Further understanding of reovirus oncolysis is critical in enhancing the clinical development and efficacy of reovirus.

Oncolytic Virotherapy for the Treatment of Malignant Glioma

“…In many tumor cells the activation of this pathway is inhibited by upregulated Ras signaling via epidermal growth factor receptor mutations [48]. While activated Ras signaling appears important to reovirus replication, the mechanism of oncolysis remains unclear and is the source of ongoing research [49].…”

Novel Function of Bluetongue Virus NS3 Protein in Regulation of the MAPK/ERK Signaling Pathway

“…Our findings could correlate with data obtained with other members of the Reoviridae family. Indeed, activation of the EGF signaling pathway has been correlated with increased reovirus replication and spread through the regulation of multiple steps of the infectious life cycle, including viral uncoating and disassembly, viral protein translation, and the generation of viral progeny (67)(68)(69). However, and in contrast to reovirus (70), we showed that the activation of the MAPK/ERK pathway by BTV-NS3 does not contribute to its ability to inhibit the induction of IFN-␣/␤.…”

Unlocking the Promise of Oncolytic Virotherapy in Glioma: Combination With Chemotherapy to Enhance Efficacy

“…Oncolytic viruses consist of both naturally occurring and genetically modified viral vectors with specificity for and propensity to kill tumor cells [7–18,34]. OVs have emerged as favorable options for glioma therapy because they have tumor and/or neurotropism, and trigger multifaceted responses including oncolysis and oncolysis-mediated stimulation of antitumor immunity, with minimal toxicity.…”

“…It does not cause any disease in adult humans and therefore is an attractive candidate for oncolytic virotherapy. Reovirus is a natural oncolytic dependent on activated Ras and its downstream effectors for tumor lysis activity, which also spares normal cells [18,34]. Although Ras signaling in cancer cells affects several events of the Reovirus replication cycle, the infectivity of Reovirus is a determining factor of oncolytic potential.…”

“…Although Ras signaling in cancer cells affects several events of the Reovirus replication cycle, the infectivity of Reovirus is a determining factor of oncolytic potential. Specifically the Ras/RalGEF/p38 axis regulates the infectivity of Reovirus, as the expression of dominant negative RalA or a p38 inhibitor renders the cancer cells (Ras activated cells which are permissive) nonpermissive to Reovirus infection [34,96]. …”