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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 Journal of thyroid research
Vol 2014
Issue
Date 2014
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
Drug Name Trade Name Synonyms Drug Classes Drug Description
Lenvatinib Lenvima E7080 FGFR Inhibitor (Pan) 23 KIT Inhibitor 53 PDGFR Inhibitor (Pan) 27 RET Inhibitor 47 VEGFR Inhibitor (Pan) 33 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
RET C634W thyroid gland 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
FGFR1 over exp thyroid gland 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