Squamous Cell Carcinomas Are Addicted to p63–FGFR2 Signaling

Activating mutations in clinically actionable oncogenes are rare in squamous cell carcinomas (SCC) of the skin, lung, esophagus, and head and neck (HNSCC), emphasizing the need to better understand the pathways driving SCC pathogenesis. SCC tumors frequently exhibit inactivation of the tumor suppressor p53 and overexpression or amplification of TP63, which encodes a p53-related transcription factor, p63, that is critical for normal epithelial development, but it is unknown how p63-regulated target genes and pathways contribute to SCC. To investigate this question, Ramsey and colleagues generated a mouse model of carcinogen-induced SCC that recapitulated many of the histologic and molecular features of human SCCs, including elevated expression of p63, in particular the ΔNp63 isoform. Tissue-specific deletion of Tp63 triggered apoptosis and rapid regression of established oral and cutaneous SCCs without significant effects on normal epithelial tissues, indicating that endogenous SCCs are dependent on p63 for survival and growth. Tp63 deficiency resulted in downregulation of genes involved in integrin signaling, RAS activation, and fibroblast growth factor (FGF) signaling, including FGF receptor 2 (Fgfr2), which was directly activated by ΔNp63 in murine SCCs and human HNSCC cell lines and correlated with Δ Np63expression in primary human HNSCCs. Consistent with a role for ΔNp63-driven FGFR2 signaling in SCC, overexpression of this p63 isoform or the FGFR2 IIIb isoform was sufficient to rescue the growth-inhibitory effects of p63 knockdown in HNSCC cells. FGFR2 activation was dependent on increased expression of FGFR2 ligands by tumor-associated stromal cells and deregulated paracrine signaling in SCC tumors. Moreover, pharmacologic inhibition of FGFR2 suppressed autochthonous SCC tumor growth via induction of apoptosis and diminished downstream AKT signaling. These findings identify a p63-regulated pathway critical for SCC tumor maintenance and suggest FGFR2 blockade as a strategy to target this oncogenic transcription factor.

Ramsey MR, Wilson C, Ory B, Rothenberg SM, Faquin W, Mills AA, et al. FGFR2 signaling underlies p63 oncogenic function in squamous cell carcinoma. J Clin Invest 2013;123:3525–38.

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