Mechanism of Action of Cabozantinib
Cabozantinib is a multi-targeted tyrosine kinase inhibitor that blocks multiple receptor tyrosine kinases including MET, VEGFR-1, -2, and -3, AXL, RET, ROS1, TYRO3, MER, KIT, TRKB, FLT-3, and TIE-2, which are involved in oncogenesis, metastasis, tumor angiogenesis, drug resistance, and maintenance of the tumor microenvironment. 1
Primary Molecular Targets
Cabozantinib inhibits the tyrosine kinase activity of several key receptors through biochemical and cellular mechanisms 1:
- VEGFR-1, -2, and -3: Blocks vascular endothelial growth factor signaling, which is critical for tumor angiogenesis 2
- MET (hepatocyte growth factor receptor): Inhibits c-MET signaling involved in tumor growth and metastasis 2, 3
- AXL: Targets this TAM (TYRO3, AXL, MER) family receptor kinase implicated in tumor progression and drug resistance 4, 3
- RET: Blocks RET kinase activity, particularly relevant in medullary thyroid cancer and RET-fusion positive cancers 5, 6, 5
- ROS1, TYRO3, MER, KIT, TRKB, FLT-3, and TIE-2: Additional receptor tyrosine kinases involved in various oncogenic pathways 1
Functional Consequences
The multi-kinase inhibition profile translates into several antitumor effects:
- Anti-angiogenic activity: Primarily through VEGFR2 inhibition, cabozantinib disrupts tumor blood vessel formation 7, 2
- Anti-metastatic effects: Preclinical studies demonstrate that cabozantinib decreases metastatic potential and tumor invasiveness more effectively than agents targeting VEGFR alone, likely due to concurrent MET inhibition 3
- Immunomodulatory properties: Cabozantinib promotes an immune-permissive tumor microenvironment by increasing neutrophil infiltration, reducing intratumor CD8+PD1+ T-cells, and decreasing regulatory T-cell infiltration 8, 9
Pharmacologic Characteristics
- Metabolism: Cabozantinib is a substrate of CYP3A4 in vitro 1
- Half-life: Approximately 99 hours at steady state 1
- Protein binding: Highly protein bound in human plasma (≥99.7%) 1
Clinical Relevance of Mechanism
The broad kinase inhibition profile explains cabozantinib's activity across multiple tumor types 10, 3, 11:
- In medullary thyroid cancer, RET inhibition is particularly important as RET mutations drive tumorigenesis 7, 2
- In renal cell carcinoma, MET and AXL inhibition addresses resistance mechanisms to VEGFR-targeted therapy 3
- In hepatocellular carcinoma, the combination of VEGFR2, MET, and AXL inhibition targets key pathways in HCC pathogenesis 9
The simultaneous inhibition of multiple pathways prevents compensatory upregulation that can occur with single-target agents, providing rationale for its efficacy in previously treated patients 3, 11.