Reference Detail

Ref Type

Journal Article

PMID

(21926191)

Authors

Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, Qian F, Chu F, Bentzien F, Cancilla B, Orf J, You A, Laird AD, Engst S, Lee L, Lesch J, Chou YC, Joly AH

Title

Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	10	12	2011 Dec	2298-308	Mol Cancer Ther

URL

Abstract Text

The signaling pathway of the receptor tyrosine kinase MET and its ligand hepatocyte growth factor (HGF) is important for cell growth, survival, and motility and is functionally linked to the signaling pathway of VEGF, which is widely recognized as a key effector in angiogenesis and cancer progression. Dysregulation of the MET/VEGF axis is found in a number of human malignancies and has been associated with tumorigenesis. Cabozantinib (XL184) is a small-molecule kinase inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3. Treatment with cabozantinib inhibited MET and VEGFR2 phosphorylation in vitro and in tumor models in vivo and led to significant reductions in cell invasion in vitro. In mouse models, cabozantinib dramatically altered tumor pathology, resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose-dependent inhibition of tumor growth in breast, lung, and glioma tumor models. Importantly, treatment with cabozantinib did not increase lung tumor burden in an experimental model of metastasis, which has been observed with inhibitors of VEGF signaling that do not target MET. Collectively, these data suggest that cabozantinib is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Cabozantinib	Cabozantinib	25	90

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Cabozantinib	Cometriq	Cabometyx\|Cabozantinib-s-malate\|XL184	AXL Inhibitor 30 FLT3 Inhibitor 66 KIT Inhibitor 57 MET Inhibitor 59 RET Inhibitor 52 ROS1 Inhibitor 20 VEGFR2 Inhibitor 37	Cometriq (Cabometyx, cabozantinib) inhibits several receptor tyrosine kinases, including VEGFR2, FLT3, AXL, MET, RET, ROS1 fusions, and c-KIT (PMID: 27370605, PMID: 21926191). Cometriq (cabozantinib) is FDA approved for use in patients with medullary thyroid cancer, Cabometyx (cabozantinib) is FDA approved for use in patients with advanced renal cell carcinoma, hepatocellular carcinoma previously treated with sorafenib, adult and pediatric patients 12 years and older with locally advanced or metastatic differentiated thyroid cancer, and in combination with Opdivo (nivolumab) in patients with advanced renal cell carcinoma (FDA.gov).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FLT3 exon 14 ins	Advanced Solid Tumor	predicted - sensitive	Cabozantinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing a FLT3-ITD mutation were sensitive to Cometriq (cabozantinib) in culture (PMID: 21926191).	21926191