Basic and Translational studies of Ras-mutant colorectal cancer

描述（由申请人提供）：每年有超过140,000名美国人被诊断患有结直肠癌（CRC），近52,000人死于结直肠癌。降低crc相关死亡的频率无疑需要根据癌症中发生的特定突变来调整个体治疗。K-Ras和N-Ras癌蛋白的激活突变在结直肠癌中很常见，并且与常规和靶向治疗的反应特别差有关。我们的首要目标是了解突变Ras蛋白致癌特性的潜在机制，以便制定有针对性的治疗策略。我们项目的前半部分将研究活化形式的Ras如何与炎症相互作用，从而影响结直肠癌的发生和进展。慢性炎症是结直肠癌的主要危险因素，我们最近发现突变的Ras可以通过NFkB途径影响信号传导（Lau等）。《科学通报》，2012)，一个重要的炎症信号通路。在本实验背景下，我们将研究突变的Ras是否会改变crc对IAP信号抑制剂的反应，IAP信号抑制剂会增强促炎细胞因子TNF-a诱导的细胞死亡。我们项目的后半部分与我们最近发现的Ras -赖氨酸乙酰化的一种新的翻译后调节机制有关。我们已经证明，乙酰化的Ras对gef诱导的核苷酸交换具有抗性，因此将核苷酸结合平衡转向gdp结合的非活性状态（Yang等）。自然科学进展。美国109:10843-10848,2012)。基于这一发现，我们现在已经确定SIRT2和HDAC6是调节Ras乙酰化状态的酶（Yang等人）。Mol. Cancer Res. In press)。在目标2中，我们将在生化水平上剖析Ras蛋白与SIRT2/HDAC6之间的相互作用，我们将确定这些去乙酰化酶的丢失如何影响突变形式Ras的致癌特性。我们预计，这种双管齐下的方法来理解Ras生物学将导致建立一个新的治疗范式k -Ras突变CRC。

DESCRIPTION (provided by applicant): 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.