More than 140,000 Americans are diagnosed with colorectal cancer (CRC) each year and almost 52,000 individuals die from it. Decreasing the frequency of CRC-related death will undoubtedly require tailoring an individual's treatment to the specific mutations that have occurred in their cancer. Activating mutations in the K-Ras and N-Ras oncoproteins are common in CRC and are associated with particularly poor response to both conventional and targeted therapies. Our overarching goal is to understand the mechanisms underlying the oncogenic properties of mutant Ras proteins in order to develop targeted therapeutic strategies. The first half of our project will examine how activated forms of Ras interact with inflammation to affect the onset and progression of CRC. Chronic inflammation is a major risk factor for CRC and we have recently shown that mutant Ras can influence signaling through the NFkB pathway (Lau et al. PLoS one 7: e41343, 2012), a major inflammatory signaling pathway. In this experimental context, we will study whether mutant Ras alters the response of CRCs to inhibitors of IAP signaling, which enhance cell death induced by the pro-inflammatory cytokine TNF-a. The second half of our project relates to our recent discovery of a novel post- translational regulatory mechanism for Ras - lysine acetylation. We have demonstrated that acetylated Ras is resistant to GEF-induced nucleotide exchange, therefore shifting the nucleotide binding equilibrium toward the GDP-bound, inactive state (Yang et al. Proc. Natl Acad. Sci. USA 109: 10843-10848, 2012). Building upon this discovery, we have now identified SIRT2 and HDAC6 as the enzymes that regulate the acetylation state of Ras (Yang et al. Mol. Cancer Res. In press).
In Aim 2, we will dissect the interaction between Ras proteins and SIRT2/HDAC6 at the biochemical level and we will determine how loss of these deacetylases affects oncogenic properties of mutant forms of Ras. We anticipate that this two-pronged approach to understanding Ras biology will lead to the establishment of a new therapeutic paradigm for K-Ras-mutant CRC.
Mutations in the K-Ras and N-Ras oncoproteins are common in colorectal cancer (CRC) and are associated with inferior response to therapy. The molecular mechanisms underlying Ras oncogenicity are poorly characterized. Using a comparative approach that includes studies of human cell lines, mouse models, and primary human samples, this project aims to address two unanswered questions related to the role that mutant Ras proteins play in the progression of CRC. First, how do mutant forms of Ras contribute to CRC in the context of chronic inflammation? Second, how is the acetylation state of Ras proteins regulated? Each of these lines of investigation could lead to the identification of new therapeutic targets for cancers expressing mutant Ras.