Synergistic Effects of Lenvatinib (E7080) and MEK Inhibitors against Anaplastic Thyroid Cancer in Preclinical Models

Abstract

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.

Advances in targeted therapy and biomarker research in thyroid cancer

“…The MAPK pathway is a signaling route that regulates cell growth, differentiation, and survival ( 115 ). MEK inhibitors are a kind of targeted therapy that interferes with the action of MEK (MAPK/ERK kinase), a critical enzyme in this pathway ( 115 ). These inhibitors are especially useful in malignancies when the MAPK pathway is dysregulated ( 115 ).…”

“…MEK inhibitors are a kind of targeted therapy that interferes with the action of MEK (MAPK/ERK kinase), a critical enzyme in this pathway ( 115 ). These inhibitors are especially useful in malignancies when the MAPK pathway is dysregulated ( 115 ). MEK inhibitors work by selectively targeting MEK, which phosphorylates and activates ERK in the MAPK pathway ( 116 ).…”

Leveraging molecular targeted drugs and immune checkpoint inhibitors treat advanced thyroid carcinoma to achieve thyroid carcinoma redifferentiation

“…Molecular targeted drugs inhibit tumor cell growth through RET/RAS/RAF/MEK/ERK and patients experienced improved radioiodine uptake in the lesion, and 5 patients showed partial response [62]. Besides, the study of selumetinib plus lenvatinib in ATC reduced tumor proliferation and increased apoptosis through the AKT and ERK signaling pathways in vitro and in vivo [63], without significant side effects. Therefore, Selumetinib has also been considered to be an effective redifferentiation agent for TC, which can enhance NIS expression and promote the reconstruction of iodine uptake ability of TC cells, restore their normal thyroidlike characteristics, and respond to iodinebased therapy [64].…”

Targeted therapy for head and neck cancer: signaling pathways and clinical studies

“…347 Although patients could significantly benefit from lenvatinib (E7080, multitarget inhibitor, mostly for VEGFR-2 (KDR)/VEGFR3 (Flt-4)), the adverse effect of lenvatinib was not tolerated in patients with radioiodine-refractory thyroid cancer. 348 Lenvatinib plus the MEK inhibitor selumetinib (AZD6244) promoted the anticancer effect in mice with anaplastic thyroid cancer. Combining selumetinib with an FGFR3 inhibitor (PD173074) significantly reduced the tumor volumes and weight in HNSCC xenografts.…”