Therapeutic Ablation of Gain-of-Function Mutant p53 in Colorectal Cancer Inhibits Stat3-Mediated Tumor Growth and Invasion

Over half of colorectal cancers (CRCs) harbor TP53 missense mutations (mutp53). We show that the most common mutp53 allele R248Q (p53Q) exerts gain of function (GOF) and creates tumor dependence in mouse CRC models. mutp53 protein binds Stat3 and enhances activating Stat3 phosphorylation by displacing the phosphatase SHP2. Ablation of the p53Q allele suppressed Jak2/Stat3 signaling, growth, and invasiveness of established, mutp53-driven tumors. Treating tumor-bearing mice with an HSP90 inhibitor suppressed mutp53 levels and tumor growth. Importantly, human CRCs with stabilized mutp53 exhibit enhanced Jak2/Stat3 signaling and are associated with poorer patient survival. Cancers with TP53R248Q/W are associated with a higher patient death risk than are those having nonR248 mutp53. These findings identify GOF mutp53 as a therapeutic target in CRC. [Display omitted] •mutp53 R248Q, the most common p53 mutant in human CRC, promotes CRC in mice•mutp53 R248Q binds to and deregulates Stat3, correlating with poor patient survival•Genetic ablation of mutp53 R248Q reduces growth and invasion of established CRCs•Hsp90 inhibition reduces the mutp53 R248Q level and inhibits CRC progression Schulz-Heddergott et al. show that the most common p53 mutant R248Q (mutp53) enhances Stat3 activation by binding to Stat3 and displacing SHP2 in colorectal cancer cells. Reduction of mutp53 genetically or by using the HSP90 inhibitor 17AAG reduces Stat3 signaling and the growth of mutp53-driven tumors.