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.