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

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 sorafenibresistant 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.

Hedgehog signaling pathway affects the sensitivity of hepatoma cells to drug therapy through the ABCC1 transporter

“…7 Primary or acquired multidrug resistance (MDR) is one of the reasons leading to HCC treatment failure and progression. 8 It is known that MDR increases drug efflux by adenosine triphosphate binding cassette (ABC) transporters, resulting in a decrease in intracellular concentrations of chemotherapeutic agents. ABCB1 (MDR-1, P-glycoprotein), ABCC1 (multidrug resistance-associated protein 1, MRP1), and ABCG2 (breast cancer-resistance protein, BCRP) are the best-characterized ABC transporters that contribute to chemoresistance.…”

Inhibition of insulin‐like growth factor 1 receptor enhances the efficacy of sorafenib in inhibiting hepatocellular carcinoma cell growth and survival

“…The IGF1R signal pathway has been reported to be enriched in sorafenib‐acquired resistant tumor cells 27. Therefore, we examined whether IGF1R remains active after sorafenib treatment in HCC cells.…”

Pharmacological Therapy of Hepatocellular Cancer Practical Issues and Solutions

“…Приобретенная резистентность к сорафенибу харак-теризуется специфическими изменениями в опухоли, о чем свидетельствует очевидное увеличение числа клеток-предшественников (Tumor-Initiating Cells), акти-вация сигнальных каскадов, специфичных для роста и выживания клетки (IGF, FGF, Myc и PI3K), неактивных в чувствительных к сорафенибу опухолях, возможность преодоления резистентности блокированием этих сиг-нальных каскадов [46]. В апреле 2016 г. регорафениб зарегистрирован FDA в качестве 2-й линии лечения сорафениб-резистентного ГЦР, в настоящее время он внесен в клинические реко-мендации многих стран.…”