Abstract A31: Targeting Oncogenic Ras Activation for Cancer Prevention

Abstract Increased Ras activity levels due to active mutations of Ras are critical for tumorigenesis. These oncogenic Ras mutations are considered to be locked in a permanent “On” state and “constitutively active”. Yet, surprisingly, expression of oncogenic Ras at physiologically levels in genetically engineered mice with “knock-in” mutant Ras has little effect on most cells. Here, we demonstrated that oncogenic K-Ras is not at all constitutively active. Rather, oncogenic K-Ras can be readily activated by upstream stimulants such as diet-induced hormones (eg. Cholecystokinin) and inflammatory stimuli (eg. PGE2 or LPS). However, unlike wild-type Ras, oncogenic K-Ras is very slow to inactivate. This effect on oncogenic K-Ras signaling kinetics leads to dramatically amplified levels of Ras activity initiated by physiologic stimuli. Sustained increase of Ras activity involves a feed-forward loop in which increased Ras activity generates more inflammatory mediators which act as Ras stimulants. High Ras activity led to acinar cell senescence and generated inflammation and fibrosis resembling the histological features of chronic inflammation with abundant precancerous lesions that spontaneously progressed to cancer only in animals expressing physiologic levels of oncogenic Ras. In summary, oncogenic Ras is not constitutively active but predisposes cells to pathological alterations dependent upon Ras activity levels. Since a large population of normal healthy humans harbors Ras mutations, in addition to targeting Ras downstream signaling pathways a reduction of factors that can activate Ras signaling may provide an important alternative cancer preventive value. These data also provide a mechanistic explanation for the link between inflammation, Ras and cancer and provide insights for cancer prevention. Citation Format: Ji Baoan, Huang Haojie, Liu Yan, Daniluk Jaroslaw, Logsdon Craig. Targeting oncogenic Ras activation for cancer prevention. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A31.