Mutated RAS: Targeting the "Untargetable" with T Cells

• Published in: Clinical cancer research Vol. 26; no. 3; pp. 537 - 544
• Main Authors: Chatani, Praveen D, Yang, James C
• Format: Journal Article
• Language: English
• Published: United States 01-02-2020
• Subjects: Humans; Immunotherapy - methods; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Molecular Targeted Therapy - methods; Mutation; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - metabolism; Neoplasms - therapy; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; T-Lymphocytes - immunology
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-19-2138

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.