Abstract PL02-01: Overcoming the undruggable nature of the most common human oncogene, K-Ras

Abstract Somatic mutations in the small GTPase K-Ras are responsible for approximately 30% of human cancers and are generally associated with poor response to standard therapies. The mutations in K-Ras were identified in the early 1980’s but it took almost four decades for the first drugs targeting the protein to be approved. The long delay was a result of the apparent lack of a drug binding pocket on K-Ras despite detailed structural and biochemical characterization of the protein, leading to it being referred to as “undruggable.” This view changed when a chemical strategy based on targeting the K-Ras (G12C) mutant common in lung cancer was successful in identifying a druggable pocket in 2013. This finding led eight years later to the approval of two new medicines for patients with K-Ras (G12C) lung cancer, sotorasib and adagrasib. One current challenge in K-Ras drug development is development of agents to inhibit the more frequent K-Ras (G12D) and K-Ras (G12V) versions found in colon and pancreatic cancer. The other challenge is drug resistance which is faced by all targeted cancer therapies including the new K-Ras (G12C) directed drugs. In this lecture I will provide a perspective on challenges and opportunities of newly developed K-Ras targeting drugs. Citation Format: Kevan M. Shokat. Overcoming the undruggable nature of the most common human oncogene, K-Ras [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr PL02-01.