Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling
TLDR
This review highlights the antitumor activity of sorafenib across a variety of tumor types, including renal cell, hepatocellular, breast, and colorectal carcinomas in the preclinical setting.Abstract:
Although patients with advanced refractory solid tumors have poor prognosis, the clinical development of targeted protein kinase inhibitors offers hope for the future treatment of many cancers. In vivo and in vitro studies have shown that the oral multikinase inhibitor, sorafenib, inhibits tumor growth and disrupts tumor microvasculature through antiproliferative, antiangiogenic, and/or proapoptotic effects. Sorafenib has shown antitumor activity in phase II/III trials involving patients with advanced renal cell carcinoma and hepatocellular carcinoma. The multiple molecular targets of sorafenib (the serine/threonine kinase Raf and receptor tyrosine kinases) may explain its broad preclinical and clinical activity. This review highlights the antitumor activity of sorafenib across a variety of tumor types, including renal cell, hepatocellular, breast, and colorectal carcinomas in the preclinical setting. In particular, preclinical evidence that supports the different mechanisms of action of sorafenib is discussed.read more
Citations
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Journal ArticleDOI
Precision medicine for hepatocellular carcinoma: driver mutations and targeted therapy
Xiao-Xiao Ding,Qing-Ge Zhu,Shi-Ming Zhang,Lei Guan,Ting Li,Lei Zhang,Shiyang Wang,Wanli Ren,Xue-Mei Chen,Jing Zhao,Song Lin,Zhi-Zhen Liu,Yanxia Bai,Bing He,Hu-Qin Zhang +14 more
TL;DR: This review summarized currently discovered driver mutations and corresponding signaling pathways, made an overview of identification methods ofDriver mutations and genes, and classified targeted drugs for HCC.
Journal ArticleDOI
ROS-mediated JNK/p38-MAPK activation regulates Bax translocation in Sorafenib-induced apoptosis of EBV-transformed B cells
TL;DR: It is reported that SRF can induce the apoptosis of EBV-transformed B cells through JNK/p38-MAPK activation and N-acetyl-l-cysteine inhibited the activation of JNK and p38- MAPK.
Journal ArticleDOI
Role of RAF/MEK/ERK pathway, p-STAT-3 and Mcl-1 in sorafenib activity in human pancreatic cancer cell lines.
Paola Ulivi,Chiara Arienti,Dino Amadori,Francesco Fabbri,Silvia Carloni,Anna Tesei,Ivan Vannini,Rosella Silvestrini,Wainer Zoli +8 more
TL;DR: The results show that sorafenib exerts anti‐proliferative and pro‐apoptotic activity in pancreatic cancer cells and could therefore represent valid treatment for Pancreatic cancer.
Journal ArticleDOI
Sorafenib sensitizes hepatocellular carcinoma cells to physiological apoptotic stimuli
Joan Fernando,Patricia Sancho,Conrado M. Fernández-Rodríguez,J. L. Lledó,Laia Caja,Jean S. Campbell,Nelson Fausto,Isabel Fabregat +7 more
TL;DR: Evidence is obtained suggesting that sorafenib effectiveness in delaying HCC late progression might be partly related to a selectively sensitization of HCC cells to apoptosis by disrupting autocrine signals that protect them from adverse conditions and pro‐apoptotic physiological cytokines.
Journal ArticleDOI
Development of a resistance-like phenotype to sorafenib by human hepatocellular carcinoma cells is reversible and can be delayed by metronomic UFT chemotherapy.
Terence C. Tang,Shan Man,Ping Xu,Giulio Francia,Kae Hashimoto,Urban Emmenegger,Urban Emmenegger,Robert S. Kerbel,Robert S. Kerbel +8 more
TL;DR: Development of a resistance-like phenotype to sorafenib is reversible, and metronomic UFT plus sorafinib may be a promising and well-tolerated treatment for increasing efficacy by delaying emergence of such 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
The Protein Kinase Complement of the Human Genome
TL;DR: The protein kinase complement of the human genome is catalogued using public and proprietary genomic, complementary DNA, and expressed sequence tag sequences to provide a starting point for comprehensive analysis of protein phosphorylation in normal and disease states and a detailed view of the current state of human genome analysis through a focus on one large gene family.
Journal ArticleDOI
Sorafenib in advanced clear-cell renal-cell carcinoma.
Bernard Escudier,Tim Eisen,Walter M. Stadler,Cezary Szczylik,Stéphane Oudard,Michael Siebels,Sylvie Negrier,Christine Chevreau,Ewa Solska,Apurva A. Desai,Frederic Rolland,Tomasz Demkow,Thomas E. Hutson,Martin Gore,Scott Freeman,Brian Schwartz,M. Shan,Ronit Simantov,Ronald M. Bukowski +18 more
TL;DR: As compared with placebo, treatment with sorafenib prolongs progression-free survival in patients with advanced clear-cell renal-cell carcinoma in whom previous therapy has failed; however, treatment is associated with increased toxic effects.
Journal ArticleDOI
BAY 43-9006 Exhibits Broad Spectrum Oral Antitumor Activity and Targets the RAF/MEK/ERK Pathway and Receptor Tyrosine Kinases Involved in Tumor Progression and Angiogenesis
Scott Wilhelm,Christopher A. Carter,LiYa Tang,Dean Wilkie,Angela McNabola,Hong Rong,Charles Chen,Xiaomei Zhang,Patrick Vincent,Mark McHugh,Yichen Cao,Jaleel Shujath,Susan Gawlak,Deepa Eveleigh,Bruce Rowley,Li Liu,Lila Adnane,Mark Lynch,Daniel Auclair,Ian W. Taylor,Rich Gedrich,Andrei Voznesensky,Bernd Riedl,Leonard Post,Gideon Bollag,Pamela A. Trail +25 more
TL;DR: Data demonstrate that BAY 43-9006 is a novel dual action RAF kinase and VEGFR inhibitor that targets tumor cell proliferation and tumor angiogenesis.
Journal ArticleDOI
Mechanism of Activation of the Raf-Erk Signaling Pathway by Oncogenic Mutations of B-Raf
Paul T C Wan,Mathew J. Garnett,S. Mark Roe,Sharlene Lee,Dan Niculescu-Duvaz,Valerie M. Good,Cancer Genome,C. Michael Jones,Christopher J. Marshall,Caroline J. Springer,David Barford,Richard Marais +11 more
TL;DR: The high activity mutants signal to ERK by directly phosphorylating MEK, whereas the impaired activity mutants stimulate MEK by activating endogenous C-RAF, possibly via an allosteric or transphosphorylation mechanism.
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