Sorafenib Mechanism of Action
Sorafenib is an oral multikinase inhibitor that works through dual mechanisms: it directly inhibits tumor cell proliferation by blocking intracellular RAF kinases (C-RAF, B-RAF, and mutant B-RAF) and the RAF/MEK/ERK signaling pathway, while simultaneously disrupting tumor angiogenesis by inhibiting multiple receptor tyrosine kinases including VEGFR-1, -2, -3, PDGFR-β, FLT-3, c-KIT, and RET. 1
Primary Mechanisms of Action
Direct Tumor Cell Inhibition
- Blocks intracellular serine/threonine kinases: Sorafenib inhibits multiple isoforms of RAF kinase (C-RAF, B-RAF, and mutant B-RAF V600E), which are critical components of the RAS/RAF/MEK/ERK signaling pathway that drives tumor cell proliferation 2, 1, 3
- Inhibits MEK and ERK phosphorylation: By blocking RAF kinases, sorafenib prevents downstream activation of MEK and ERK in cancer cell lines and tumor xenografts, resulting in decreased tumor cell proliferation 3
- Induces apoptosis: Sorafenib promotes tumor cell death by reducing eIF4E phosphorylation and downregulating Mcl-1 levels, a key anti-apoptotic protein 4, 5
Anti-Angiogenic Effects
- Inhibits VEGF receptor family: Sorafenib blocks VEGFR-1, VEGFR-2, and VEGFR-3, which are essential for tumor neovascularization and angiogenesis 2, 1
- Blocks PDGF signaling: Inhibition of PDGFR-β disrupts tumor vasculature development and maintenance 2, 3
- Reduces tumor microvasculature: These anti-angiogenic effects lead to decreased tumor blood supply and regression of newly formed microvessels 4, 3
Additional Kinase Targets
Beyond RAF and VEGF receptors, sorafenib inhibits several other kinases involved in tumor progression:
- FLT-3: Involved in hematopoietic cell proliferation 2, 1
- c-KIT: Plays a role in tumor cell signaling and growth 2, 1
- RET and RET/PTC: Implicated in certain thyroid cancers 2, 1
Clinical Implications
The dual mechanism allows sorafenib to attack tumors from two angles simultaneously:
- Direct tumor inhibition through RAF/MEK/ERK pathway blockade reduces tumor cell proliferation and induces apoptosis 3, 5
- Indirect tumor suppression through anti-angiogenic effects starves tumors of nutrients and oxygen by disrupting blood vessel formation 4, 3
This multikinase inhibition profile explains sorafenib's FDA approval for advanced renal cell carcinoma and unresectable hepatocellular carcinoma, where both tumor cell proliferation and angiogenesis are critical for disease progression 1, 4
Pharmacodynamic Effects
In preclinical models, sorafenib demonstrated:
- Inhibition of tumor growth in HCC and differentiated thyroid cancer xenografts 1
- Reductions in tumor angiogenesis in HCC models 1
- Increases in tumor apoptosis in HCC and differentiated thyroid cancer models 1
Human studies showed no large QTc interval changes (>20 ms) at therapeutic doses of 400 mg twice daily 1