Abstract IA10: K-RAS hyperexchange mutants in colorectal cancer

Abstract

Abstract K-RAS can be functionally activated by reducing its ability to catalyze the hydrolysis of GTP and/or by increasing its nucleotide exchange activity. Cancer-associated mutations that increase exchange – termed hyperexchange mutants – are relatively rare and exhibit unique structural, biochemical, and biologic properties relative to hydrolysis mutants. The most common hyperexchange mutant is Ala146Thr, which exhibits a 10-fold increase in exchange activity relative to wild-type K-RAS while not significantly affecting GTP hydrolysis. This mutant is relatively common in colorectal cancer, but exceedingly rare in pancreatic cancer. The hyperexchange property of K-RASA146T leads to relatively low steady state levels of K-RAS-GTP, which underlies the tissue specific oncogenic activity of the mutant. Another hyperexchange mutant, K-RASA59T, is unique in that it uses the gamma-phosphate of GTP to phosphorylate Thr59 in the active site. This mutant also exhibits attenuated MAPK signaling, but through a distinct mechanism. K-RAS proteins with oncogenic substitutions at position 59 fail to properly engage RAF proteins and cannot induce B-RAF/C-RAF dimers. As a result, residue 59 mutants require cooperating mutations in other MAPK pathway genes in order to be fully oncogenic. This obligate cooperativity is borne out in the genetics of human cancers and in genetically engineered mouse models. In summary, hyperexchange mutants represent a class of oncogenic forms of K-RAS that exhibit distinct biochemically properties and attenuated MAPK. As such, this class of mutants may be sensitive to therapeutic approaches that are not effective in cancers expressing stronger forms of oncogenic K-RAS. Citation Format: Kevin Haigis. K-RAS hyperexchange mutants in colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr IA10.