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

结直肠癌(CRC)是西方世界主要的癌症类型。不幸的是，对结直肠癌患者的有效治疗仍然有限。近50%的结直肠癌患者共有的一个特殊分子特征是，通常保护身体免受恶性细胞积累的p53肿瘤抑制基因发生了突变。突变型P53不仅失去了抑癌功能，而且成为促进肿瘤发展和转移的基因/蛋白。在人类结直肠癌中，95%的P53突变是DNA结合域的错义突变，经常产生构象异常的蛋白(突变P53)。重要的是，正如我们的结果所显示的那样，几乎所有的突变P53蛋白都表现出显著的稳定性，尤其是在癌细胞中，因为它们受到一种名为HSP90的伴侣蛋白复合体的保护。此外，我们发现突变p53癌细胞似乎对其高度稳定的突变p53上瘾以求生存，因为急性基因移除会杀死这些细胞。这表明突变的p53是一个潜在的重要的临床靶点。我们小组的数据显示，一类新的小分子HSP90抑制剂(SAHA)或后期临床试验(17AAG)会破坏突变P53的稳定性。这个项目的主要问题是，已建立的肿瘤是否需要稳定的突变P53的持续表达来维持它们。为了严格地探讨这个问题，我们将分析一个突变p53的结直肠癌小鼠模型和人类CRC癌细胞株，其中突变p53可以被随意移除。我们将把所取得的治疗效果与HSP90抑制剂对突变P53的药理降解进行比较。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普遍的癌蛋白突变型p53是否是维持肿瘤所必需的，并概述了一种有前景的新策略，使其在最常见的人类癌症中具有药理靶向。

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.