Mutated RAS: Targeting the Untargetable with T Cells

The RAS family of proteins is at the apex of several pathways implicated in a multitude of epithelial cancers but has remained stubbornly resistant to the wave of targeted small molecules and antibodies that have revolutionized clinical oncology. KRAS, the most commonly mutated of the isoforms, represents an attractive target for treatment, given its ubiquity, central role as a driver mutation, and association with poor prognosis. This review is a comprehensive summary of the existing approaches to targeting KRAS spanning small-molecule inhibitors, cancer vaccines, and with a focus on trials in adoptive cell therapy. Here we explain how the limitations of existing drugs and nonspecific immune-based therapies are circumvented with techniques in modern immunotherapy. The successes outlined represent the most promising path to finally targeting the prototypical undruggable RAS oncogene family.