Tumour initiating cells and IGF/FGF signalling contribute to sorafenib resistance in hepatocellular carcinoma. Issue 3 (11th December 2015)

• Record Type: Journal Article
• Authors: Tovar, Victoria; Cornella, Helena; Moeini, Agrin; Vidal, Samuel; Hoshida, Yujin; Sia, Daniela; Peix, Judit; Cabellos, Laia; Alsinet, Clara; Torrecilla, Sara; Martinez-Quetglas, Iris; Lozano, Juan José; Desbois-Mouthon, Christèle; Solé, Manel; Domingo-Domenech, Josep; Villanueva, Augusto; Llovet, Josep M
• Is Part Of: Gut. Volume 66:Issue 3(2017)
• Page Start: 530
• Page End: 540
• Publication Date: 2015-12-11
• Subjects: HEPATOCELLULAR CARCINOMA -- DRUG RESISTANCE -- MOLECULAR MECHANISMS -- STEM CELLS -- MOLECULAR GENETICS; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2015-309501
• Languages: English
• ISSNs: 0017-5749

Abstract

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), p<0.001. Tumours with sorafenib-acquired resistance were enriched with insulin-like growth factor (IGF) and fibroblast growth factor (FGF) signalling cascades (false discovery rate (FDR)<0.05). In vitro, cells derived from sorafenib-acquired resistant tumours and two sorafenib-resistant HCC cell lines were responsive to IGF or FGF inhibition. In vivo, FGF blockade delayed tumour growth and improved survival in sorafenib-resistant tumours. A sorafenib-resistance 175 gene signature was characterised by enrichment of progenitor cell features, aggressive tumorous traits and predicted poor survival in two cohorts (n=442 patients with HCC). Conclusions: 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.