期刊
GUT
卷 66, 期 3, 页码 530-539出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/gutjnl-2015-309501
关键词
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资金
- Bristol-Myers Squibb
- European Commission [667273-2, 259744]
- Samuel Waxman Cancer Research Foundation
- Spanish National Health Institute [SAF-2013-41027]
- Asociacion Espanola Contra el Cancer (AECC)
- AECC
- Instituto de Salud Carlos III (PFIS programme)
- Spanish National Health Institute (FPI programme)
- Italian Association for Cancer Research
- Italian National Ministry of Health
- U.S. National Institute of Diabetes and Digestive and Kidney Diseases [R01 DK099558]
- French institute of health and medical research (INSERM)
- French Institute of Cancer (INCA) [INCa-DGOS_5790]
- ICREA Funding Source: Custom
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.
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