PT  - JOURNAL ARTICLE
AU  - Victoria Tovar
AU  - Helena Cornella
AU  - Agrin Moeini
AU  - Samuel Vidal
AU  - Yujin Hoshida
AU  - Daniela Sia
AU  - Judit Peix
AU  - Laia Cabellos
AU  - Clara Alsinet
AU  - Sara Torrecilla
AU  - Iris Martinez-Quetglas
AU  - Juan José Lozano
AU  - Christèle Desbois-Mouthon
AU  - Manel Solé
AU  - Josep Domingo-Domenech
AU  - Augusto Villanueva
AU  - Josep M Llovet
TI  - Tumour initiating cells and IGF/FGF signalling contribute to sorafenib resistance in hepatocellular carcinoma
AID  - 10.1136/gutjnl-2015-309501
DP  - 2017 Mar 01
TA  - Gut
PG  - 530--540
VI  - 66
IP  - 3
4099  - http://gut.bmj.com/content/66/3/530.short
4100  - http://gut.bmj.com/content/66/3/530.full
SO  - Gut2017 Mar 01; 66
AB  - 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.