Journal ArticleDOI
Hepatocellular carcinoma and sorafenib: too many resistance mechanisms?
TLDR
The promising systemic treatment has demonstrated limited survival benefits with very low rates of tumour response, suggesting the existence of primary and acquired drug resistance mechanisms, and HCC appears to be a moving target.Abstract:
Hepatocellular carcinoma (HCC), the most common tumour of the liver, develops in more than 80% of cases on patients with chronically damaged livers owing to excessive alcohol consumption, hepatitis B or C virus (HBV or HCV) infection or obesity. Despite positive results of HBV vaccination programmes and the promising data from the new anti-HCV treatments,1 the incidence of HCC is increasing significantly in Western countries because of the progression of old HCV infections and the almost epidemic prevalence of obesity and metabolic syndrome-associated non-alcoholic fatty liver disease.2
The prognosis of patients with HCC is generally very poor. HCC tumours are resistant to chemotherapy and are usually diagnosed at a late stage when the curative strategies of surgical resection and orthotopic liver transplantation are not applicable. Targeted treatments against specific oncogenes have been shown to be effective in the treatment of leukaemias and solid tumours such as breast, colon and lung carcinomas.3 In 2008, the SHARP (Sorafenib HCC Assessment Randomised Protocol) trials showed an improved overall survival in Child–Pugh class A patients with advanced HCC upon treatment with the antiangiogenic and antiproliferative agent sorafenib.4 This multikinase inhibitor was established as the standard of care for patients with advanced HCC. However, the promising systemic treatment has demonstrated limited survival benefits with very low rates of tumour response, suggesting the existence of primary and acquired drug resistance mechanisms.5
In this situation HCC appears to be a moving target, and a rapid intervention in at …read more
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Journal ArticleDOI
Tumor-Associated Neutrophils Recruit Macrophages and T-Regulatory Cells to Promote Progression of Hepatocellular Carcinoma and Resistance to Sorafenib.
Shao-Lai Zhou,Zheng-Jun Zhou,Zhi-Qiang Hu,Xiao-Wu Huang,Zheng Wang,Er-Bao Chen,Jia Fan,Ya Cao,Zhi Dai,Jian Zhou +9 more
TL;DR: TAN-conditioned media, as well as recombinant CCL2 and CCL17, increased the migratory activity of the macrophages and T-regulatory cells from patients or mice with HCC to a greater extent that PBN- conditioned media.
Journal ArticleDOI
In vivo RNAi screening identifies a mechanism of sorafenib resistance in liver cancer
Ramona Rudalska,Daniel Dauch,Thomas Longerich,Katherine McJunkin,Torsten Wuestefeld,Tae-Won Kang,Anja Hohmeyer,Marina Pesic,Josef Leibold,Anne von Thun,Peter Schirmacher,Johannes Zuber,Karl-Heinz Weiss,Scott Powers,Nisar P. Malek,Martin Eilers,Bence Sipos,Scott W. Lowe,Robert Geffers,Stefan Laufer,Lars Zender +20 more
TL;DR: A system that enables pooled shRNA screening directly in mouse hepatocellular carcinomas in vivo to identify genes likely to be involved in therapy resistance is described, suggesting that a combination of sorafenib and Mapk14 blockade is a promising approach to overcoming therapy resistance of human HCC.
Journal ArticleDOI
Inhibition of Akt Reverses the Acquired Resistance to Sorafenib by Switching Protective Autophagy to Autophagic Cell Death in Hepatocellular Carcinoma
Bo Zhai,Fengli Hu,Xian Jiang,Jun Xu,Dali Zhao,Bing Liu,Shangha Pan,Xuesong Dong,Gang Tan,Zheng Wei,Haiquan Qiao,Hongchi Jiang,Xueying Sun +12 more
TL;DR: Results have provided evidence for clinical investigation of GDC0068, a novel ATP-competitive pan-Akt inhibitor, as the second-line treatment after the failure of sorafenib-medicated molecular targeted therapy for advanced HCC.
Journal ArticleDOI
Inflammation and Liver Cancer: Molecular Mechanisms and Therapeutic Targets.
TL;DR: The role of cytokine signals, NF-κB, JNK, innate and adaptive immunity, and hepatic stellate cells in HCC are highlighted and whether these pathways could be therapeutic targets are discussed.
Journal ArticleDOI
MicroRNA-122 confers sorafenib resistance to hepatocellular carcinoma cells by targeting IGF-1R to regulate RAS/RAF/ERK signaling pathways.
Yanmin Xu,Ji Huang,Leina Ma,Juanjuan Shan,Junjie Shen,Zhi Yang,Limei Liu,Yongli Luo,Chao Yao,Cheng Qian +9 more
TL;DR: The results indicated that activation of IGF-1R by ectopic down-regulation of miR-122 counteracted the effects of sorafenib-induced apoptosis, thus conferring sorAFenib resistance.
References
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Journal ArticleDOI
Sorafenib in Advanced Hepatocellular Carcinoma
Josep M. Llovet,Sergio Ricci,Vincenzo Mazzaferro,Philip Hilgard,Edward Gane,Jean-Frédéric Blanc,André Cosme de Oliveira,Armando Santoro,Jean-Luc Raoul,Alejandro Forner,Myron Schwartz,Camillo Porta,Stefan Zeuzem,Luigi Bolondi,Tim F. Greten,Peter R. Galle,Jean Francois Seitz,Ivan Borbath,Dieter Häussinger,Tom Giannaris,Minghua Shan,M. Moscovici,D. Voliotis,Jordi Bruix +23 more
TL;DR: In patients with advanced hepatocellular carcinoma, median survival and the time to radiologic progression were nearly 3 months longer for patients treated with sorafenib than for those given placebo.
Journal ArticleDOI
Role of the Microenvironment in the Pathogenesis and Treatment of Hepatocellular Carcinoma
Virginia Hernandez–Gea,Virginia Hernandez–Gea,Sara Toffanin,Scott L. Friedman,Josep M. Llovet +4 more
TL;DR: Increasing the understanding of how stromal components interact with cancer cells and the signaling pathways involved could help identify new therapeutic and chemopreventive targets.
Journal ArticleDOI
A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer.
King Pan Ng,Axel M. Hillmer,Charles Chuah,Charles Chuah,Wen Chun Juan,Tun Kiat Ko,Audrey S.M. Teo,Pramila N. Ariyaratne,Naoto Takahashi,Kenichi Sawada,Yao Fei,Yao Fei,Sheila Soh,Wah Heng Lee,John W.J. Huang,John Carson Allen,Xing Yi Woo,Niranjan Nagarajan,Vikrant Kumar,Anbupalam Thalamuthu,Wan Ting Poh,Ai Leen Ang,Hae Tha Mya,Gee Fung How,L.Y. Yang,Liang Piu Koh,Balram Chowbay,Chia-Tien Chang,V. S. Nadarajan,Wee Joo Chng,Hein Than,Lay Cheng Lim,Yeow Tee Goh,Shenli Zhang,Dianne Poh,Patrick Tan,Patrick Tan,Ju Ee Seet,Mei-Kim Ang,Noan-Minh Chau,Quan Sing Ng,Daniel Shao-Weng Tan,Manabu Soda,Kazutoshi Isobe,Markus M. Nöthen,Tien Yin Wong,Atif Shahab,Xiaoan Ruan,Valere Cacheux-Rataboul,Wing-Kin Sung,Eng Huat Tan,Yasushi Yatabe,Hiroyuki Mano,Hiroyuki Mano,Ross A. Soo,Tan Min Chin,Wan-Teck Lim,Yijun Ruan,Yijun Ruan,S. Tiong Ong +59 more
TL;DR: The results offer an explanation for the heterogeneity of TKI responses across individuals and suggest the possibility of personalizing therapy with BH3 mimetics to overcome BIM-polymorphism–associated TKI resistance.
Journal ArticleDOI
Inhibition of autophagy potentiates the antitumor effect of the multikinase inhibitor sorafenib in hepatocellular carcinoma.
Satoshi Shimizu,Tetsuo Takehara,Hayato Hikita,Takahiro Kodama,Hinako Tsunematsu,Takuya Miyagi,Atsushi Hosui,Hisashi Ishida,Tomohide Tatsumi,Tatsuya Kanto,Naoki Hiramatsu,Naonobu Fujita,Tamotsu Yoshimori,Norio Hayashi +13 more
TL;DR: Investigation of the role of autophagy, an evolutionarily conserved self‐digestion pathway, in hepatoma cells in vitro and in vivo found it to be an attractive strategy for unlocking the antitumor potential of sorafenib in HCC.
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Sorafenib in Advanced Hepatocellular Carcinoma
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