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Original Article
Tumour initiating cells and IGF/FGF signalling contribute to sorafenib resistance in hepatocellular carcinoma
  1. Victoria Tovar1,
  2. Helena Cornella1,
  3. Agrin Moeini1,
  4. Samuel Vidal2,
  5. Yujin Hoshida3,
  6. Daniela Sia1,3,4,
  7. Judit Peix1,
  8. Laia Cabellos1,
  9. Clara Alsinet1,
  10. Sara Torrecilla1,
  11. Iris Martinez-Quetglas1,
  12. Juan José Lozano5,
  13. Christèle Desbois-Mouthon6,7,
  14. Manel Solé1,
  15. Josep Domingo-Domenech2,
  16. Augusto Villanueva3,8,
  17. Josep M Llovet1,3,9
  1. 1Liver Cancer Translational Research Laboratory, Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit and Pathology Department, IDIBAPS, Hospital Clínic, CIBERehd, Universitat de Barcelona, Barcelona, Spain
  2. 2Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, USA
  3. 3Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
  4. 4Gastrointestinal Surgery and Liver Transplantation Unit, National Cancer Institute, Milan, Italy
  5. 5Bioinformatic Platform, IDIBAPS, CIBERehd, Barcelona, Spain
  6. 6Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, Saint-Antoine Research Center, Paris, France
  7. 7INSERM UMR_S 938, Saint-Antoine Research Center, Paris, France
  8. 8Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, USA
  9. 9Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
  1. Correspondence to Dr Josep M Llovet, Liver Cancer Translational Research Laboratory, BCLC Group, IDIBAPS, Liver Unit, Hospital Clínic, University of Barcelona, Villarroel 170, Barcelona 08036, Spain; jmllovet{at}clinic.cat

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.

  • HEPATOCELLULAR CARCINOMA
  • DRUG RESISTANCE
  • MOLECULAR MECHANISMS
  • STEM CELLS
  • MOLECULAR GENETICS

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