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Gut. 2017 Mar;66(3):530-540. doi: 10.1136/gutjnl-2015-309501. Epub 2015 Dec 11.

Tumour initiating cells and IGF/FGF signalling contribute to sorafenib resistance in hepatocellular carcinoma.

Author information

1
Liver 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
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, USA.
3
Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA.
4
Gastrointestinal Surgery and Liver Transplantation Unit, National Cancer Institute, Milan, Italy.
5
Bioinformatic Platform, IDIBAPS, CIBERehd, Barcelona, Spain.
6
Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, Saint-Antoine Research Center, Paris, France.
7
INSERM UMR_S 938, Saint-Antoine Research Center, Paris, France.
8
Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, USA.
9
Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.

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.

KEYWORDS:

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

PMID:
26658144
PMCID:
PMC5600200
DOI:
10.1136/gutjnl-2015-309501
[Indexed for MEDLINE]
Free PMC Article

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