A conditional mutant p53 allele in a mouse model of colorectal cancer: oncogene addiction and drug target evaluation

结直肠癌（CRC）是西方世界的主要癌症类型。不幸的是，CRC患者的有效治疗仍然有限。近50%的CRC患者共有的一个特定分子特征是，通常保护身体免受恶性细胞积聚的p53肿瘤抑制基因发生突变。突变p53不仅失去了其肿瘤抑制功能，但成为一个肿瘤促进基因/蛋白，可能有助于CRC的进展和转移。95%的p53突变在人类CRC的DNA结合域的错义突变，经常产生构象异常蛋白（mutp 53）。重要的是，几乎所有的mutp 53蛋白质都表现出显着的稳定性，特别是在癌细胞中，因为它们被称为HSP 90的伴侣蛋白复合物保护，正如我们的结果所示。此外，我们发现mutp 53癌细胞似乎依赖于其超稳定的mutp 53来生存，因为急性基因去除会杀死这些细胞。这将mutp 53确定为潜在的重要临床靶点。来自我们小组的数据表明，mutp 53被一类新的小分子HSP 90抑制剂破坏稳定，这些抑制剂已经上市（SAHA）或处于后期临床试验（17 AAG）中。这个项目的主要问题是，是否建立肿瘤需要稳定的mutp 53的持续表达，以维持其。为了严格探索这个问题，我们将分析mutp 53结肠直肠癌小鼠模型和人类CRC癌细胞系，其中mutp 53可以随意去除。我们将比较所获得的治疗效果与HSP 90抑制剂对mutp 53的药理学降解。总之，该项目旨在全面评估临床关键问题，即人类恶性肿瘤中最常见的癌蛋白突变型p53是否是肿瘤维持所需的，并概述了一种有前途的新策略，用于其在最常见的人类癌症之一中的药理学靶向。

Colorectal cancer (CRC) is a leading cancer type in the Western world. Unfortunately, effective therapies for patients with CRC remains limited. One specific molecular feature that is shared by nearly 50% of CRC patients is that the p53 tumor suppressor gene that normally protects the body from accumulating malignant cells undergoes mutations. Mutant p53 not only has lost its tumor supressor function but becomes a tumor-promoting gene/protein that likely contributes to CRC progression and metastasis.95% of p53 mutations in human CRC are missense mutations in the DNA-binding domain that frequently generate conformationally abnormal proteins (mutp53). Importantly, nearly all mutp53 proteins exhibit dramatic stabilization specifically in cancer cells because they are protected by a chaperone protein complex called HSP90, as our results showed. Moreover, we find that mutp53 cancer cells appear to be addicted to their hyperstable mutp53 for survival, since acute genetic removal kills such cells. This identifies mutp53 as a potentially significant clinical target. Data from our group show that mutp53 is destabilized by a new class of small-molecule HSP90 inhibitors which are already on the market (SAHA) or in late clinical trials (17AAG). The main question of this project is whether established tumors require continued expression of stabilized mutp53 for their maintenance. To rigorously explore this question, we will analyze a mutp53 mouse model of colorectal cancer and human CRC cancer cell lines where mutp53 can be removed at will. We will compare the achieved therapeutic effects to pharmacological degradation of mutp53 by HSP90 inhibitors. In sum, this project aims at the comprehensive evaluation of the clinically critical question whether the most prevalent oncoprotein in human malignancies, mutant p53, is required for tumor maintenance and outlines a promising new strategy for its pharmacological targeting in one of the most common human cancers.