Reference Detail

Ref Type

Journal Article

PMID

(25295214)

Authors

Tohyama O, Matsui J, Kodama K, Hata-Sugi N, Kimura T, Okamoto K, Minoshima Y, Iwata M, Funahashi Y

Title

Antitumor activity of lenvatinib (e7080): an angiogenesis inhibitor that targets multiple receptor tyrosine kinases in preclinical human thyroid cancer models.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of thyroid research	2014		2014	638747	J Thyroid Res

URL

Abstract Text

Inhibition of tumor angiogenesis by blockading the vascular endothelial growth factor (VEGF) signaling pathway is a promising therapeutic strategy for thyroid cancer. Lenvatinib mesilate (lenvatinib) is a potent inhibitor of VEGF receptors (VEGFR1-3) and other prooncogenic and prooncogenic receptor tyrosine kinases, including fibroblast growth factor receptors (FGFR1-4), platelet derived growth factor receptor α (PDGFRα), KIT, and RET. We examined the antitumor activity of lenvatinib against human thyroid cancer xenograft models in nude mice. Orally administered lenvatinib showed significant antitumor activity in 5 differentiated thyroid cancer (DTC), 5 anaplastic thyroid cancer (ATC), and 1 medullary thyroid cancer (MTC) xenograft models. Lenvatinib also showed antiangiogenesis activity against 5 DTC and 5 ATC xenografts, while lenvatinib showed in vitro antiproliferative activity against only 2 of 11 thyroid cancer cell lines: that is, RO82-W-1 and TT cells. Western blot analysis showed that cultured RO82-W-1 cells overexpressed FGFR1 and that lenvatinib inhibited the phosphorylation of FGFR1 and its downstream effector FRS2. Lenvatinib also inhibited the phosphorylation of RET with the activated mutation C634W in TT cells. These data demonstrate that lenvatinib provides antitumor activity mainly via angiogenesis inhibition but also inhibits FGFR and RET signaling pathway in preclinical human thyroid cancer models.

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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
Lenvatinib	Lenvatinib	11	35

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Lenvatinib	Lenvima	E7080	FGFR Inhibitor (Pan) 26 KIT Inhibitor 57 PDGFR Inhibitor (Pan) 30 RET Inhibitor 52 VEGFR Inhibitor (Pan) 36	Lenvima (lenvatinib) inhibits VEGFR, FGFR, PDGFR, KIT, and RET, and suppresses cell proliferation and angiogenesis (PMID: 21781317, PMID: 25295214, PMID: 17943726). Lenvima (lenvatinib) is FDA approved for use in patients with radioactive iodine-refractory differentiated thyroid cancer, unresectable hepatocellular carcinoma, in combination with Keytruda (pembrolizumab) as first line, or with Afinitor (everolimus) for renal cell carcinoma, and in combination with Pembrolizumab for endometrial carcinoma that is not MSI-H or dMMR (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
FGFR1 over exp	thyroid cancer	sensitive	Lenvatinib	Preclinical	Actionable	In a preclinical study, Lenvima (lenvatinib) inhibited FGFR1 phosphorylation and signaling in thyroid cancer cells overexpressing FGFR1 (PMID: 25295214).	25295214
RET C634W	thyroid cancer	sensitive	Lenvatinib	Preclinical	Actionable	In a preclinical study, Lenvima (lenvatinib) inhibited RET phosphorylation and signaling in thyroid cancer cells expressing RET C634W (PMID: 25295214).	25295214