Tumor cells with activated RAS signaling and defective interferon antiviral pathways

Tumor cells with activated RAS signaling and defective interferon antiviral pathways represent a specific cellular phenotype exploited by oncolytic virotherapy. In normal cells, viral infection triggers the production of interferon (IFN) and the activation of Protein Kinase R (PKR), which halts protein synthesis to prevent viral spread [1]. However, in many cancers, constitutive activation of the RAS/MAPK pathway inhibits PKR, while concomitant defects in the IFN signaling pathway further impair the cell's innate ability to mount an antiviral response [2]. This creates a permissive intracellular environment that allows certain viruses, such as the mammalian orthoreovirus, to selectively replicate and induce lysis in malignant cells while sparing healthy tissue [3]. The drug Pelareorep (Reolysin) is a naturally occurring reovirus that specifically targets this vulnerability in various cancers, including pancreatic and colorectal malignancies [4]. Consequently, this phenotype serves as a functional target for viral-based immunotherapies, where the therapeutic window is defined by the loss of host defense mechanisms rather than the presence of a specific surface receptor [5]. Citations: [1] Strong, J. E., et al. (1998). "The molecular basis of viral oncolysis: usurpation of the Ras signaling pathway by reovirus." EMBO J. [2] Stojdl, D. F., et al. (2000). "Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus." Cancer Cell. [3] Shmulevitz, M., et al. (2005). "Genetic and determinants of reovirus oncolysis." Cancer Gene Therapy. [4] Gong, J., et al. (2016). "Pelareorep: a first-in-class oncolytic virus for the treatment of solid tumors." Investigational New Drugs. [5] Norman, K. L., & Lee, P. W. (2000). "Not all viruses are bad: orthoreovirus as a cancer therapeutic." Gene Therapy.

Other names

RAS-activated cancer cellsIFN-deficient tumor cellsReovirus-susceptible cellsRAS-transformed cells

Selective viral replication and oncolysis in cells where activated RAS signaling inhibits PKR-mediated antiviral responses and defective interferon signaling prevents innate immune defense.