Abstract
Simple SummaryLenvatinib has been found to be effective against radioiodine-refractory thyroid cancer. However, compliance with lenvatinib therapy is poor due to cancer progression and adverse effects. To improve the success rate of lenvatinib treatment, we propose a combination of lenvatinib and another drug class that has a different target than lenvatinib. We tested the potential of this combination in preclinical models and found that it is effective in our models. The combination also does not cause significant adverse effects in our mouse model. Thus, our results suggest that the combination we propose in this study is a potential therapeutic approach for thyroid cancer that is not responsive to radiotherapy.E7080, known as lenvatinib, is an oral multitargeted tyrosine kinase inhibitor that has been shown to improve the survival rate of patients with radioiodine-refractory thyroid cancer. However, a majority of patients do not continue lenvatinib intake due to disease progression or significant toxicity. To improve treatment success rates, we propose the combination of lenvatinib with mitogen-activated protein kinase (MEK) inhibitors. To test this hypothesis, we tested the effects of lenvatinib with the MEK inhibitor U0126 in vitro using two human anaplastic thyroid cancer (ATC) cell lines, 8505C and TCO1, and with another MEK inhibitor, selumetinib (AZD6244), in an ATC mouse model. We found that the combination of lenvatinib with MEK inhibitors enhanced the antitumor effects of monotherapy with either agent in vitro and in vivo, and these effects may be through the AKT (Protein Kinase B) and extracellular signal-regulated kinase (ERK) signaling pathways. Furthermore, the combination does not have significant adverse effects in the ATC mouse models in terms of body weight, blood biochemical parameters, and histopathology. In conclusion, the combination of lenvatinib with an MEK inhibitor is a potentially viable therapeutic approach for ATC treatment.
Highlights
IntroductionThyroid cancer (TC) is the most common endocrine carcinoma, with reported incidence of 12.9 per 100,000 individuals in the United States (2011–2015) and 25.8 per
Because lenvatinib suppressed AKT signaling but did not inhibit mitogen-activated protein kinase (MAPK) signaling, we investigated the effects of the combination of lenvatinib with U0126, an mitogen-activated protein kinase (MEK)
extracellular signal-regulated kinase (ERK) phosphorylation and suppressed cyclin D1 expression (Figure 2E–J). These results indicate that lenvatinib and an MEK inhibitor exhibit synergistic inhibition of AKT and MAPK signaling in vitro
Summary
Thyroid cancer (TC) is the most common endocrine carcinoma, with reported incidence of 12.9 per 100,000 individuals in the United States (2011–2015) and 25.8 per. The incidence of TC has substantially increased in several countries, and this increase is attributed to diagnostic imaging and fine-needle aspiration [2]. Mild invasion, with an overall survival rate of over 90% within 10 years [3,4,5,6,7]. Among the RAI-refractory TCs, anaplastic thyroid cancer (ATC) is the most aggressive, displaying rapid tumor growth, local invasion, and frequent distant metastasis, and the 6-month survival rates for ATC were reported to be only 26.6% and 6.6% for TNM stages IVB and IVC, respectively [8,9,10]
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