Abstract 279: Increased Met receptor activation mediates enhanced cell invasion upon mutant p53 expression in esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC), a type of squamous cell cancer, is one of the most aggressive forms of human cancer with poor prognosis due to late diagnosis and metastasis. Common genomic alterations in ESCC include p53 mutations and overexpression of oncogenes such as cyclin D1, EGFR, and Met. Using an invasive primary esophageal epithelial cell model system genetically transformed by the overexpression of EGFR and p53 R175H , we find novel evidence of cross-talk between p53 R175H and the Met receptor tyrosine kinase. Increased Met receptor activation is observed upon expression of p53 R175H and is further enhanced upon subsequent overexpression of EGFR. Increased Met activation is observed also in a number of human ESCC cells lines that harbor either p53 genetic mutations or are p53 null. Met phosphorylation can be inhibited using two small molecule compounds (CP31398 and 5-iminodaunorubicin) that have been demonstrated previously to activate wild-type p53 signaling through distinct mechanisms, thereby providing further evidence to a link between these two pathways. Both CP31398 and 5-iminodaunorubicin blocked invasion of the genetically transformed primary esophageal epithelial cells (EPC-hTERT-EGFR-p53 R175H ) suggesting that the mechanism of increased invasiveness upon EGFR and p53 R175H expression may be mediated by Met activation. In aggregate, mutant p53 and Met appear to cooperate to foster tumor invasion and this novel linkage has not been reported previously. These results provide further implications to the use of combinatorial therapeutics directed at Met and mutant p53 in ESCC and other squamous cell cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 279.