Modeling KRAS genetic heterogeneity in mouse models

 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CRC。降低CRC相关死亡的频率无疑需要针对癌症中发生的特定突变量身定制个体治疗。K-Ras癌蛋白的激活突变在CRC中很常见，并且与对常规和靶向治疗的反应特别差有关。例如，突变型K-Ras与抗EGFR治疗耐药性之间的强相关性导致美国临床肿瘤学会建议所有癌症患者在接受治疗前进行K-Ras突变检测。然而，新的临床和实验数据已经对与突变型K-Ras相关的治疗抗性的普遍性提出了质疑。与K-Ras野生型患者一样，具有特定K-Ras激活突变（如G13 D）的患者似乎从抗EGFR治疗中获益。基于我们在小鼠模型中研究Ras突变CRC的专业知识（Haigis等人，Nat.Genet. 40：600-608，2008; Wang等人Cancer Disc. 3：294-307，2013），我们将对特定K-Ras突变和治疗反应之间的关系进行深入分析。这项工作分为四个相关的具体目标：（1）全面表征K-Ras突变谱并鉴定原发性人CRC中的共发生突变，（2）在小鼠中产生Cre依赖性K-Ras激活等位基因的等位基因系列，（3）测量CRC小鼠模型中与不同K-Ras突变相关的分子、细胞和组织水平表型，（4）评价EGFR和MEK抑制剂在表达不同突变型K-Ras等位基因的CRC小鼠模型中的疗效。最后，该项目中开发的K-Ras突变小鼠模型将揭示CRC患者的遗传亚群，这些亚群将受益于特定的靶向治疗。

 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 oncoprotein are common in CRC and are associated with particularly poor response to both conventional and targeted therapies. For example, the strong association between mutant K-Ras and resistance to anti-EGFR therapy led the American Society for Clinical Oncology to recommend that all cancer patients undergo K-Ras mutation testing prior to receiving treatment. Nevertheless, new clinical and experimental data have called into question the universality of therapeutic resistance associated with mutant K-Ras. Patients with specific K-Ras activating mutations, such as G13D, appear to benefit from anti-EGFR therapy, just like K-Ras wild-type patients. Building upon our expertise in studying Ras-mutant CRC in mouse models (Haigis et al. Nat. Genet. 40: 600-608, 2008; Wang et al. Cancer Disc. 3: 294-307, 2013), we will perform an in-depth analysis of the relationship between specific K-Ras mutations and therapeutic response. This work is separated into four related specific aims: (1) To comprehensively characterize the K-Ras mutational spectrum and to identify co-occurring mutations in primary human CRCs, (2) To generate an allelic series of Cre-dependent K-Ras activating alleles in mice, (3) To measure the molecular, cellular, and tissue-level phenotypes associated with different K-Ras mutations in a mouse model of CRC, and (4) To evaluate the efficacy of EGFR and MEK inhibitors in mouse models of CRC expressing different mutant alleles of K-Ras. In the end, the K-Ras mutant mouse models developed in this project will reveal genetic subpopulations of CRC patients that will benefit from specific targeted therapies.