The Effects of Four Different Tyrosine Kinase Inhibitors on Medullary and Papillary Thyroid Cancer Cells

Verbeek, Hans H. G.; Alves, Maria M.; Groot, Jan-Willem B de; Osinga, Jan; Plukker, John; Links, Thera P.; Hofstra, Robert

doi:10.1210/jc.2010-2381

Cited by 74 publications

(53 citation statements)

References 22 publications

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“…Cabozantinib is a potent inhibitor of RET kinase activity and the proliferation of TT cells in vitro. Our results for inhibition of TT cell proliferation are concordant with those of a previous study, which also showed that cabozantinib is a significantly more potent inhibitor of TT cell proliferation than vandetanib, sunitinib, or axitinib (50). In vivo pharmacodynamic studies showed substantial inhibition of RET in TT xenograft tumors following a single oral dose of cabozantinib.…”

Section: Cabozantinib Inhibits Tt Tumor Growthsupporting

confidence: 91%

“…Given the evidence for co-expression of MET and RET in MTC tumor tissue, we characterized the ability of cabozantinib to inhibit the kinase activity of three mutated RET variants found in MTC patients. In biochemical assays, cabozantinib inhibited the RETactivating kinase domain mutation M918T with an IC 50 of 27 nmol/L, and to a lesser extent the Y791F mutant (IC 50 1173 nmol/L). Cabozantinib was not active against the RET mutant V804L (IC 50 > 5000 nmol/L) previously shown to render resistance to other RET inhibitors (43).…”

Section: Cabozantinib Is a Potent Inhibitor Of Ret In Vitromentioning

confidence: 98%

“…Specifically, inhouse generated recombinant HIS-tagged human wild type RET M700-D1042 and M918T RET M707-D1014 fusion proteins and recombinant GST-tagged V804L and Y791F RET (Invitrogen, Carlsbad, CA) fusion proteins expressed in sf9 cells were utilized. Half-maximal inhibitory concentration (IC 50 ) values were determined by measuring phosphorylation of the substrate poly(Glu, Tyr) peptide at ATP concentrations at or below the Km for each respective kinase.…”

Section: Kinase Inhibition Assaysmentioning

confidence: 99%

“…2A). Based on the dose-response relationship, the predicted plasma concentration that results in 50% inhibition (IC 50 ) of phosphorylation of RET in this xenograft model is 1572 BENTZIEN ET AL.…”

Section: Cabozantinib Inhibits Ligand-independent Phosphorylation Of mentioning

confidence: 99%

“…We note that in PTC, RET is activated by translocation in approximately 30-40% of adult patients (16,53), and that our data (this report) and that of others (23,24) show that MET overexpression is also a common feature of PTC. Cabozantinib has been reported to be a potent inhibitor of the proliferation of a PTC cell line bearing a RET-PTC translocation (50). A preliminary investigation of cabozantinib in PTC patients suggests that there is clinical activity in this tumor type (54), and further investigation is planned.…”

Section: Cabozantinib Inhibits Tt Tumor Growthmentioning

confidence: 99%

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In Vitro and In Vivo Activity of Cabozantinib (XL184), an Inhibitor of RET, MET, and VEGFR2, in a Model of Medullary Thyroid Cancer

Bentzien

Zuzow

Heald

et al. 2013

Thyroid

114

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Background: A limited number of approved therapeutic options are available to metastatic medullary thyroid cancer (MTC) patients, and the response to conventional chemotherapy and/or radiotherapy strategies is inadequate. Sporadic and inherited mutations in the tyrosine kinase RET result in oncogenic activation that is associated with the pathogenesis of MTC. Cabozantinib is a potent inhibitor of MET, RET, and vascular endothelial factor receptor 2 (VEGFR2), as well as other tyrosine kinases that have been implicated in tumor development and progression. The object of this study was to determine the in vitro biochemical and cellular inhibitory profile of cabozantinib against RET, and in vivo antitumor efficacy using a xenograft model of MTC. Methods: Cabozantinib was evaluated in biochemical and cell-based assays that determined the potency of the compound against wild type and activating mutant forms of RET. Additionally, the pharmacodynamic modulation of RET and MET and in vivo antitumor activity of cabozantinib was examined in a MTC tumor model following subchronic oral administration. Results: In biochemical assays, cabozantinib inhibited multiple forms of oncogenic RET kinase activity, including M918T and Y791F mutants. Additionally, it inhibited proliferation of TT tumor cells that harbor a C634W activating mutation of RET that is most often associated with MEN2A and familial MTC. In these same cells grown as xenograft tumors in nude mice, oral administration of cabozantinib resulted in dose-dependent tumor growth inhibition that correlated with a reduction in circulating plasma calcitonin levels. Moreover, immunohistochemical analyses of tumors revealed that cabozantinib reduced levels of phosphorylated MET and RET, and decreased tumor cellularity, proliferation, and vascularization. Conclusions: Cabozantinib is a potent inhibitor of RET and prevalent mutationally activated forms of RET known to be associated with MTC, and effectively inhibits the growth of a MTC tumor cell model in vitro and in vivo.

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Section: Cabozantinib Inhibits Tt Tumor Growthsupporting

confidence: 91%

Section: Cabozantinib Is a Potent Inhibitor Of Ret In Vitromentioning

confidence: 98%

Section: Kinase Inhibition Assaysmentioning

confidence: 99%

Section: Cabozantinib Inhibits Ligand-independent Phosphorylation Of mentioning

confidence: 99%