mTOR inhibition improves fibroblast growth factor receptor targeting in hepatocellular carcinoma

• Published in: British journal of cancer Vol. 112; no. 5; pp. 841 - 850
• Main Authors: Scheller, T, Hellerbrand, C, Moser, C, Schmidt, K, Kroemer, A, Brunner, S M, Schlitt, H J, Geissler, E K, Lang, S A
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 03.03.2015
• Subjects: Angiogenesis; Animals; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - pathology; Cell culture; Cell growth; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Drug Synergism; Fibroblasts; Gene Expression Regulation, Neoplastic - drug effects; Hep G2 Cells; Hospitals; Humans; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - pathology; Medical prognosis; Mice; Mice, Nude; Motility; Neoplasm Transplantation; Phenylurea Compounds - administration & dosage; Phenylurea Compounds - pharmacology; Pyrimidines - administration & dosage; Pyrimidines - pharmacology; Receptor, Fibroblast Growth Factor, Type 1 - antagonists & inhibitors; Signal Transduction - drug effects; Sirolimus - administration & dosage; Sirolimus - pharmacology; Surgery; TOR Serine-Threonine Kinases - antagonists & inhibitors; Translational Therapeutics; Vascular endothelial growth factor; Xenograft Model Antitumor Assays; United States > US; Germany
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2014.638

Systemic therapy has proven only marginal effects in hepatocellular carcinoma (HCC) so far. The aim of this study was to evaluate the effect of targeting fibroblast growth factor receptor (FGFR) on tumour and stromal cells in HCC models. Human and murine HCC cells, endothelial cells (ECs), vascular smooth muscle cells (VSMCs), hepatic stellate cells (HSCs), human HCC samples, FGFR inhibitor BGJ398 and mammalian target of rapamycin (mTOR) inhibitor rapamycin were used. Effects on growth, motility, signalling and angiogenic markers were determined. In vivo subcutaneous and syngeneic orthotopic tumour models were used. In tumour cells and ECs, targeting FGFR showed significant inhibitory effects on signalling and motility. Minor effects of FGFR inhibition were observed on VSMCs and HSCs, which were significantly enhanced by combining FGFR and mTOR blockade. In vivo daily (5 mg kg(-1)) treatment with BGJ398 led to a significant growth inhibition in subcutaneous tumour models, but only a combination of FGFR and mTOR blockade impaired tumour growth in the orthotopic model. This was paralleled by reduced tumour cell proliferation, vascularisation, pericytes and increased apoptosis. Targeting FGFR with BGJ398 affects tumour cells and ECs, whereas only a combination with mTOR inhibition impairs recruitment of VSMCs and HSCs. Therefore, this study provides evidence for combined FGFR/mTOR inhibition in HCC.