Abstract
Abstract Transcription factors mediate diverse functions in normal development and tumorigenesis. The p53-related transcription factor p63 (TP63) plays an essential role in development of stratified epithelial tissues, as germline loss of p63 leads to abnormal proliferation and differentiation of ectoderm-derived precursors. The role of p63 in human cancer, however, is controversial. Loss of p63 is associated with neoplastic progression in some animal models and in a subset of human tumors. Nevertheless, p63 is rarely targeted for somatic mutational inactivation and is indeed overexpressed in squamous cell carcinomas (SCCs), where is has been postulated to function either as a key tumor maintenance factor or as a lineage marker not essential to the malignant process. Here, we show that SCCs are profoundly dependent on p63 expression in vivo, and we identify a key, therapeutically relevant pathway through which p63 mediates tumor maintenance. Conditional genetic ablation of p63 in an endogenous SCC model induces rapid and dramatic tumor regression owing to apoptosis of p63-expressing cells. We identify the FGFR2 oncogene as a direct transcriptional target of p63 that signals through AKT to mediate survival of SCC cells. Finally, we employ the clinical FGFR2 inhibitor AZD4547 to demonstrate the potential therapeutic effect of extinguishing FGFR2 signaling in p63-expressing SCCs. These results define p63 as a key tumor maintenance factor through regulation of FGFR2 signaling in SCC. More broadly, this demonstrates the potential for targeting oncogenic transcription factor pathways in tumors such as SCC that rarely exhibit somatic oncogene-activating mutations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1306. doi:1538-7445.AM2012-1306
Published Version
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