Ras and exosome signaling

Abstract

Ras gene (HRAS, NRAS, and KRAS) has been observed to be mutated and hyper-activated in a significant proportion of cancers. However, mutant Ras remains a challenging therapeutic target. Similarly, inhibition of targets upstream and downstream of Ras has shown limited clinical utility. There have been attempts to develop and deliver mutant K-Ras silencing RNAs either through their encapsulation in liposomes or nanoparticles. However, these approaches show very limited success due to the lack of stability of such carrier molecules alongside associated toxicity. There is a pressing need for the identification of better therapeutic targets for Ras or its associated pathways as well as improvements in the design of superior RNAi delivery systems to suppress mutant K-Ras. More than a decade ago, it was shown that aggregates of palmitoylated Ras isoforms (H-Ras and N-Ras) passage through the cytosol on rapidly moving nanosized particles ("rasosomes"). Fast forward a decade, considerable new knowledge has emerged in the area of small vesicles, microparticles, and exosomes. Exosomes are tiny vesicles and play a significant role in regulating cancer-related signaling pathways. Exosomes have also been studied as delivery vehicles to transport drugs, proteins, and microRNAs of choice for therapeutic purposes. K-Ras pathway proteins have been implicated in exosome biogenesis and extravasation processes. This review provides an update on the current knowledge related to K-Ras signaling and exosomes and also discusses how these tiny vesicles can be harnessed to successfully deliver the K-Ras silencing moieties.

Keywords: Exosomes; Kras; Mutant Kras; RNAi; Ras; Therapeutic drug delivery; Vesicles.