Tumour initiating cells and IGF/FGF signalling contribute to sorafenib resistance in hepatocellular carcinoma
Open Access
- 11 December 2015
- Vol. 66 (3), 530-540
- https://doi.org/10.1136/gutjnl-2015-309501
Abstract
Objective Sorafenib is effective in hepatocellular carcinoma (HCC), but patients ultimately present disease progression. Molecular mechanisms underlying acquired resistance are still unknown. Herein, we characterise the role of tumour-initiating cells (T-ICs) and signalling pathways involved in sorafenib resistance. Design HCC xenograft mice treated with sorafenib (n=22) were explored for responsiveness (n=5) and acquired resistance (n=17). Mechanism of acquired resistance were assessed by: (1) role of T-ICs by in vitro sphere formation and in vivo tumourigenesis assays using NOD/SCID mice, (2) activation of alternative signalling pathways and (3) efficacy of anti-FGF and anti-IGF drugs in experimental models. Gene expression (microarray, quantitative real-time PCR (qRT-PCR)) and protein analyses (immunohistochemistry, western blot) were conducted. A novel gene signature of sorafenib resistance was generated and tested in two independent cohorts. Results Sorafenib-acquired resistant tumours showed significant enrichment of T-ICs (164 cells needed to create a tumour) versus sorafenib-sensitive tumours (13 400 cells) and non-treated tumours (1292 cells), pConclusions Acquired resistance to sorafenib is driven by T-ICs with enrichment of progenitor markers and activation of IGF and FGF signalling. Inhibition of these pathways would benefit a subset of patients after sorafenib progression.Keywords
This publication has 38 references indexed in Scilit:
- Brivanib, a Dual FGF/VEGF Inhibitor, Is Active Both First and Second Line against Mouse Pancreatic Neuroendocrine Tumors Developing Adaptive/Evasive Resistance to VEGF InhibitionClinical Cancer Research, 2011
- Improved Survival with Vemurafenib in Melanoma with BRAF V600E MutationThe New England Journal of Medicine, 2011
- Combining Clinical, Pathology, and Gene Expression Data to Predict Recurrence of Hepatocellular CarcinomaGastroenterology, 2011
- Acquired Resistance to BRAF Inhibitors Mediated by a RAF Kinase Switch in Melanoma Can Be Overcome by Cotargeting MEK and IGF-1R/PI3KCancer Cell, 2010
- IGF activation in a molecular subclass of hepatocellular carcinoma and pre-clinical efficacy of IGF-1R blockageJournal of Hepatology, 2010
- Ras pathway activation in hepatocellular carcinoma and anti-tumoral effect of combined sorafenib and rapamycin in vivoJournal of Hepatology, 2009
- Pivotal Role of mTOR Signaling in Hepatocellular CarcinomaGastroenterology, 2008
- Focal Gains of VEGFA and Molecular Classification of Hepatocellular CarcinomaCancer Research, 2008
- Sorafenib in Advanced Hepatocellular CarcinomaThe New England Journal of Medicine, 2008
- The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem CellsCell, 2008