MTORC1 and FGFR1 signaling in fibrolamellar hepatocellular carcinoma

Abstract

Fibrolamellar hepatocellular carcinoma, or fibrolamellar carcinoma, is a rare form of primary liver cancer that afflicts healthy young men and women without underlying liver disease. There are currently no effective treatments for fibrolamellar carcinoma other than resection or transplantation. In this study, we sought evidence of mechanistic target of rapamycin complex 1 (mTORC1) activation in fibrolamellar carcinoma, based on anecdotal reports of tumor response to rapamycin analogs. Using a tissue microarray of 89 primary liver tumors, including a subset of 10 fibrolamellar carcinomas, we assessed the expression of phosphorylated S6 ribosomal protein (P-S6), a downstream target of mTORC1, along with fibroblast growth factor receptor 1 (FGFR1). These results were extended and confirmed using an additional 13 fibrolamellar carcinomas, whose medical records were reviewed. In contrast to weak staining in normal livers, all fibrolamellar carcinomas on the tissue microarray showed strong immunostaining for FGFR1 and P-S6, whereas only 13% of non-fibrolamellar hepatocellular carcinomas had concurrent activation of FGFR1 and mTORC1 signaling (P<0.05). When individual samples were stratified according to staining intensity (scale 0-4), the average score in fibrolamellar carcinomas was 2.46 for FGFR1 and 3.77 for P-S6, compared with 0 and 0, respectively, in non-tumor liver. Immunoblot analyses of fibrolamellar carcinomas revealed high mTORC1 activities relative to AKT activities accompanied by reduced TSC2 expression, which was not observed in non-fibrolamellar hepatocellular carcinomas. Our findings provide evidence for mTORC1 activation and FGFR1 overexpression in human fibrolamellar carcinoma, and support the use of FGFR1 inhibitors and rapamycin analogs in the treatment of patients with unresectable fibrolamellar carcinoma.