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

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

High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses

“…11 Three subsequent phase I studies underscored this evidence by demonstrating consistent activity of sorafenib in relapsed and refractory FLT3-ITD AML, while primary resistance was frequently seen in AML expressing the wild-type form of FLT3. [12][13][14] Thus, although sorafenib simultaneously blocks FLT3 and multiple other kinases, such as the serine threonine kinase Raf-1, plateletderived growth factor receptor and vascular endothelial growth factor receptor, 15 its most relevant target in AML appears to be FLT3-ITD.…”

Efficacy and Safety of Sorafenib for Advanced Non-Small Cell Lung Cancer: a Meta-analysis of Randomized Controlled Trials

“…Others such as c-Raf, b-Raf, c-Kit and Flt3 are also key members of critical pathways for cell proliferation, differentiation and apoptosis (Kemmer et al, 2004;Kindler et al, 2010;Maurer et al, 2011;Berk et al, 2013). Sorafenib may have anti-tumor activities through a dual mechanism, acting indirectly on the tumor angiogenesis via VEGFR/PDGFR pathways and directly on tumor growth by inhibition Raf/Kit/Flt3 signaling (Wilhelm et al, 2008).…”

Drug therapy: Sorafenib

“…Preclinical models have demonstrated the ability of Sorafenib to do both, but the actual effects in human tissue have not been assessed. 22 As mentioned, two large randomized studies, one conducted in Europe and North America, and a second in Asia, have proven a benefit for sorafenib in BCLC Stage C liver cancer. Importantly, both studies required well-compensated liver disease (Child-Pugh A) at study entry.…”

“…20,21 Sorafenib is an oral, small molecule tyrosine kinase inhibitor of several intracellular proteins suspected to be important in tumor progression, including the platelet derived growth factor receptor-b (PDGFR), raf kinase, and the vascular endothelial growth factor receptors (VEGFR) including VEGFR-1, VEGFR-2, and VEGFR-3. 22 The proposed mechanism of action of sorafenib is shown in Fig. 2.…”