Victoria Tovar1, Helena Cornella1, Agrin Moeini1, Samuel Vidal2, Yujin Hoshida3, Daniela Sia1,3,4, Judit Peix1, Laia Cabellos1, Clara Alsinet1, Sara Torrecilla1, Iris Martinez-Quetglas1, Juan José Lozano5, Christèle Desbois-Mouthon6,7, Manel Solé1, Josep Domingo-Domenech2, Augusto Villanueva3,8, Josep M Llovet1,3,9. 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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/SCIDmice, (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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
Authors: Pippa Newell; Sara Toffanin; Augusto Villanueva; Derek Y Chiang; Beatriz Minguez; Laia Cabellos; Radoslav Savic; Yujin Hoshida; Kiat Hon Lim; Pedro Melgar-Lesmes; Steven Yea; Judit Peix; Kemal Deniz; M Isabel Fiel; Swan Thung; Clara Alsinet; Victoria Tovar; Vincenzo Mazzaferro; Jordi Bruix; Sasan Roayaie; Myron Schwartz; Scott L Friedman; Josep M Llovet Journal: J Hepatol Date: 2009-06-12 Impact factor: 25.083
Authors: Cho-Hao Lin; Khadija H Elkholy; Nissar A Wani; Ding Li; Peng Hu; Juan M Barajas; Lianbo Yu; Xiaoli Zhang; Samson T Jacob; Wasif N Khan; Xue-Feng Bai; Anne M Noonan; Kalpana Ghoshal Journal: Mol Cancer Ther Date: 2019-10-03 Impact factor: 6.261
Authors: Ming Jin; Ye Yang; Yi Dai; Rong Cai; Liunan Wu; Yuwen Jiao; Zhan Zhang; Haojun Yang; Yan Zhou; Liming Tang; Lei Li; Yuan Li Journal: Cell Biol Toxicol Date: 2021-04-20 Impact factor: 6.691
Authors: Dhwanil A Dalwadi; Laura Torrens; Jordi Abril-Fornaguera; Roser Pinyol; Catherine Willoughby; Jeffrey Posey; Josep M Llovet; Christian Lanciault; David W Russell; Markus Grompe; Willscott E Naugler Journal: Mol Ther Date: 2020-10-22 Impact factor: 11.454