The brief introduction of Sorafenib

Description

Sorafenib is a multikinase inhibitor that has recently obtained Food and Drug Administration (FDA) approval for the treatment of advanced renal cell carcinoma (RCC). It has been tried in several solid tumors, including HCC. A recent phase III trial has shown that sorafenib significantly extends survival for patients with advanced HCC[1].It is NOT a chemotherapy drug. It is a targeted 'magic bullet' type of therapy and is used to treat people with kidney cancer that has spread outside the kidney.

Biological function

Sorafenib is a member of the class of phenylureas that is urea in which one of the nitrogens is substituted by a 4-chloro-3-trifluorophenyl group while the other is substituted by a phenyl group which, in turn, is substituted at the para position by a [2-(methylcarbamoyl)pyridin-4-yl]oxy group.It has a role as an antineoplastic agent, an EC 2.7.11.1 (non-specific serine/threonine protein kinase) inhibitor, a tyrosine kinase inhibitor, an angiogenesis inhibitor, an anticoronaviral agent and a ferroptosis inducer. It is a pyridinecarboxamide, a member of monochlorobenzenes, an aromatic ether, a member of (trifluoromethyl)benzenes and a member of phenylureas.

Mechanism of action

Sorafenib is an inhibitor of several kinases involved in both tumor cell proliferation (tumor growth) and angiogenesis (tumor blood supply). These include Raf, VEGFR and PDGFR.Raf is serine/theonine kinase, which when activated by Ras (membrane localized protein) stimulates gene transcription in the nucleus, leading to a variety of tumor-promoting cellular effects. VEGF is the primary mediator of both normal and tumor-associated angiogenesis. It exerts this effect through several mechanisms, including induction of endothelial cell division and migration, promotion of endothelial cell survival through protection from apoptosis, and reversal of endothelial cell aging. VEGF interacts with receptors (VEGFR 1,2,3) present on the endothelial cell surface, which leads to autophosphorylation of intracellular receptor tyrosine kinase, and a cascade of downstream proteins is activated[2]. PDGF has its receptor on the surface of capillary endothelial cells. The binding of PDGF to the receptors has several effects on endothelial cell motility and apoptosis.

Side effects

The most common treatment-related toxicities include diarrhoea, fatigue, hand-foot skin reaction and hypertension. Most of these toxicities are considered mild to moderate and manageable to varying degrees; however, cardiovascular events might lead to death[3].

References

[1] Weiwei Tang. “The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects.” Signal Transduction and Targeted Therapy (2020): 87.

[2] Giorgia Marisi. “Ten years of sorafenib in hepatocellular carcinoma: Are there any predictive and/or prognostic markers?” World Journal of Gastroenterology (2018): 4152–4163.

[3] Meyer, Tim. “Treatment of advanced hepatocellular carcinoma: beyond sorafenib.” Lancet Gastroenterology & Hepatology (2018): 218–220.