Mechanism of action
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CABOMETYX® (cabozantinib) targets 3 key drivers of aRCC, HCC, and DTC tumorigenesis—MET, AXL, and VEGFR1*†
- In aRCC, HCC, and DTC tumor cells and cells of the tumor microenvironment, MET, AXL, and VEGF are overexpressed2-8
- These receptors are involved in normal and pathologic processes such as tumor angiogenesis, invasiveness, metastasis, and immunomodulation of the tumor microenvironment1,3,7,9-15

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Mechanism of action shown is based on in vitro biochemical and/or cellular assays. The clinical significance is unknown.1
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As seen in preclinical models; cabozantinib has also been shown to inhibit ROS1, TYRO3, MER, KIT, TRKB, FLT-3, and TIE-2.1
aRCC=advanced renal cell carcinoma; AXL=growth arrest-specific protein 6 receptor; FLT-3=FMS-like tyrosine kinase 3; HCC=hepatocellular carcinoma; KIT=KIT receptor tyrosine kinase; MER=MER receptor tyrosine kinase; MET=mesenchymal epithelial transition kinase; RCC=renal cell carcinoma; RET=RET receptor tyrosine kinase; ROS1=ROS1 receptor tyrosine kinase; TIE-2=tyrosine kinase with Ig and EGF homology domains-2; TKl=tyrosine kinase inhibitor; TRKB=tropomyosin receptor kinase B; TYRO3=TYRO3 protein tyrosine kinase; VEGF=vascular endothelial growth factor; VEGFR=vascular endothelial growth factor receptor.
References:
- CABOMETYX® (cabozantinib) Prescribing Information. Exelixis, Inc.
- Rankin EB, Fuh KC, Castellini L, et al. Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET. Proc Natl Acad Sci USA. 2014;111(37):13373-13378.
- Zhou L, Liu X-D, Sun M, et al. Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma. Oncogene. 2016;35(21):2687-2697. doi:10.1038/onc.2015.343.
- Kwilas AR, Ardiani A, Donahue RN, et al. Dual effects of a targeted small-molecule inhibitor (cabozantinib) on immune-mediated killing of tumor cells and immune tumor microenvironment permissiveness when combined with a cancer vaccine. J Transl Med. 2014;12:294.
- Tannir NM, Schwab G, Grünwald V. Cabozantinib: an active novel multikinase inhibitor in renal cell carcinoma. Curr Oncol Rep. 2017;19(2):1-8. doi:10.1007/s11912-017-0566-9.
- Goyal L, Muzumdar MD, Zhu AX. Targeting the HGF/c-MET pathway in hepatocellular carcinoma. Clin Cancer Res. 2013;19(9):2310-2318. doi:10.1158/1078-0432.CCR-12-2791.
- Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379(1):54-63. doi:10.1056/NEJMoa1717002.
- Graham DK, Deryckere D, Davies KD, Earp HS. The TAM family: phosphatidylserine-sensing receptor tyrosine kinases gone awry in cancer. Nat Rev Cancer. 2014;14(12):769-785. doi:10.1038/nrc3847.
- Bukowski RM. Third generation tyrosine kinase inhibitors and their development in advanced renal cell carcinoma. Front Oncol. 2012;2(13):1-10.
- Koochekpour S, Jeffers M, Wang PH, et al. The von Hippel-Lindau tumor suppressor gene inhibits hepatocyte growth factor/scatter factor-induced invasion and branching morphogenesis in renal carcinoma cells. Mol Cell Biol. 1999;19(9):5902-5912.
- Aguilera TA, Giaccia AJ. Molecular pathways: oncologic pathways and their role in T-cell exclusion and immune evasion—a new role for the AXL receptor tyrosine kinase. Clin Cancer Res. 2017;23(12):2928-2933. doi:10.1158/1078-0432.ccr-17-0189.
- Aguilera TA, Rafat M, Castellini L, et al. Reprogramming the immunological microenvironment through radiation and targeting AXL. Nat Commun. 2016;7(13898):1-14. doi:10.1038/ncomms13898.
- Ilangumaran S, Villalobos-Hernandez A, Bobbala D, Ramanathan S. The hepatocyte growth factor (HGF)-MET receptor tyrosine kinase signaling pathway: diverse roles in modulating immune cell functions. Cytokine. 2016;82:125-139. doi:10.1016/j.cyto.2015.12.013.
- Hubel J, Hieronymus T. HGF/MET-signaling contributes to immune regulation by modulating tolerogenic and motogenic properties of dendritic cells. Biomedicines. 2015;3(1):138-148. doi:10.3390/biomedicines3010138.
- Yang J, Yan J, Liu B. Targeting VEGF/VEGFR to modulate antitumor immunity. Front Immunol. 2018;9(978):1-9. doi:10.3389/fimmu.2018.00978.