Abstract LB-031: Biochemical profiling of cancer-associated KRAS mutants: clues towards an understanding of differential clinical outcomes

Abstract

Abstract As one of the first identified and most commonly activated oncogenes, V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) has been a focus of cancer research for many decades. Despite progress in our understanding of RAS biology, significant questions remain unanswered regarding observed differences in clinical outcomes between tumors harboring different KRAS mutations. In an attempt to understand these clinical differences we characterized the pertinent biochemical properties of the most commonly observed KRAS mutants including, nucleotide exchange rate, intrinsic and GTPase activating protein (GAP)-stimulated GTP hydrolysis rate and affinity for one of the enzyme's primary downstream effectors, Raf kinase. We additionally solved high resolution crystal structures of four of these mutants and attempt to explain the observed biochemical differences between the mutants in the context of these structures. Based on the individual biochemical properties of each KRAS mutant, we propose a classification scheme to predict the propensity of the various mutants to activate Raf-kinase and respond to therapies targeting this downstream signaling pathway. Citation Format: John C. Hunter, Deepak Gurbani, Martin Carrasco, Anuj Manandhar, Sudershan Gondi, Kenneth Westover. Biochemical profiling of cancer-associated KRAS mutants: clues towards an understanding of differential clinical outcomes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-031. doi:10.1158/1538-7445.AM2015-LB-031