Abstract 1387: The importance of FGF pathway in hepatocellular carcinoma and its role in acquired resistance to anti-angiogenic therapies

Abstract

Abstract INTRODUCTION: Fibroblast Growth Factor (FGF) signaling has an important role in different biological functions and human cancers, being some of its members described as driver oncogenes and components of evasive resistance to anti-angiogenic therapies. AIMS: 1) To identify molecular alterations of FGF signaling in human hepatocellular carcinoma (HCC), 2) to study the mechanism of acquired resistance to anti-angiogenic therapy in HCC to identify novel targets, and 3) to evaluate the role of brivanib in overcoming acquired resistance in animal models of HCC. METHODS: FGF pathway was analyzed in 104 early HCCs by whole-genome expression, genome-wide methylation status, microRNA expression and chromosomal aberrations. Subcutaneous tumors in nude mice (n=26) were treated with sorafenib (30 mg/kg/day) until development of acquired resistance, afterwards mice were randomized into either brivanib (BMS, 100 mg/kg/day) or sorafenib treatment. Anti-tumoral effect and survival were assessed. The mechanisms involved in acquired resistance were studied by gene expression profiling and protein evaluation. RESULTS: 31% of the HCC samples presented overexpression of oncogenic ligands (i.e. FGF19, FGF 21 and FGF2), and 19% overexpression of FGFR3 and FGFR4 -feature clustered in the proliferation HCC subclass (Chiang, Cancer Res, 2008). Promoter hypermethylation of FGFR2 (FDR=0.015) and regulation of FGFR3 expression by miR-483-5p (6 fold-change, FDR<0.05) were also observed, as well as high level amplification in FGF19 locus (8% of samples), and allelic losses of FGFR2 and Spry2 (p<0.05). FGF2 overexpression was associated with WNT-beta-catenin HCC subclass and correlated with expression of WNT-liver specific targets (i.e. GLUL, LGR5, TBX3, SPARCL1, p<0.05) suggesting a crosstalk among FGF and WNT pathways in HCC. Regarding the in vivo model, 65% mice acquired resistance after sorafenib therapy [median: 42 days; tumor size: 855 mm3 resistant group vs 316 mm3 sorafenib-responder group (p=0.002)]. This acquired resistance phenotype has been evaluated by gene profiling and GSEA revealing an enrichment of gene signatures of poor prognosis and resistance to cancer therapies (FDR<0.05), and identifying IGF-1R and FGFR1 overexpression as the potential drivers of the development of this resistance. Brivanib delayed tumor growth (p=0.03), increased survival after development of acquired resistance (median survival: 32 days vs 15 days on sorafenib, p=0.07) and inhibited FGF downstream signaling, reverting the resistant phenotype. CONCLUSIONS: FGF pathway is activated in a subclass of early HCC due to deregulation of ligands and receptors by different mechanisms. Acquired resistance to sorafenib in experimental models seems to be driven by FGF and IGF signaling pathways. Brivanib significantly delayed tumor growth and increased survival in the sorafenib-resistant in vivo model. 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 1387. doi:1538-7445.AM2012-1387