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

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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.