Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling

By S. Wilhelm, Lila Adnane, P. Newell, A. Villanueva, J. Llovet, M. Lynch. Molecular Cancer Therapeutics, 2008

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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. [Mol Cancer Ther 2008;7(10):3129–40]

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/60d2cb57abc393b9526d91f0f644b42a4e6551e2

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EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. (2012, background): “No selective Ras/ERK/MAPK inhibitor has been approved, but sorafenib and regorafenib have shown partial cascade blockage [311].”
Sorafenib or placebo plus TACE with doxorubicin-eluting beads for intermediate stage HCC: The SPACE trial. (2016, background): “Sorafenib is a multikinase inhibitor [22–24] shown in two large, double-blind, randomized, placebo-controlled phase III clinical trials to significantly improve OS and time-to-tumor progression (TTP) in patients with advanced HCC [25,26].”
Pharmacological inhibition of cystine–glutamate exchange induces endoplasmic reticulum stress and ferroptosis (2014, background): “Despite sorafenib's multi-kinase inhibitory activity, there is disagreement about whether the sorafenib lethal mechanism of action in cells involves kinase inhibition or binding to an alternative target (Wilhelm et al., 2008).”
New Perspectives on How to Discover Drugs from Herbal Medicines: CAM's Outstanding Contribution to Modern Therapeutics (2013, background): “Nexavar, an orally active multikinase inhibitor, was originally designed to inhibit Raf kinase isoforms for treating renal and liver cancers, but it was also found to inhibit PDGF and VEGF receptor tyrosine kinases [175].”
Exosomes derived from miR-122-modified adipose tissue-derived MSCs increase chemosensitivity of hepatocellular carcinoma (2015, background): “Given that systemic therapy with the multikinase inhibitor sorafenib is the standard of care for unresectable or advanced-stage HCC [28], we further tested whether 122-Exo can synergize its inhibitory function in mice model.”
EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. (2012, background): “No selective Ras/ERK/MAPK inhibitor has been approved, but sorafenib and regorafenib have shown partial cascade blockage [311].”