Abstract
Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI) that shows improved median progression-free survival (PFS) in patients with thyroid carcinomas. However, virtually all patients ultimately progress, indicating the need for a better understanding of the mechanisms of resistance. Here, we examined the molecular profile of anaplastic thyroid cancer cells (8505C) exposed to lenvatinib and found that long-term exposure to lenvatinib caused phenotypic changes. Consistent with change toward mesenchymal morphology, activation of pro-survival signaling, nuclear exporter protein exportin 1 (XPO1) and Rho GTPase effector p21 activated kinases (PAK) was also observed. RNA-seq analysis showed that prolonged lenvatinib treatment caused alterations in numerous cellular pathways and several oncogenes such as CEACAM (carcinoembryonic antigen-related cell adhesion molecule) and NUPR1 (Nuclear protein 1) were also upregulated. Further, we evaluated the impact of XPO1 and PAK4 inhibition in the presence or absence of lenvatinib. Targeted inhibition of XPO1 and PAK4 could sensitize the 8505C cells to lenvatinib. Both XPO1 and PAK4 inhibitors, when combined with lenvatinib, showed superior anti-tumor activity in 8505C sub-cutaneous xenograft. These studies bring forward novel drug combinations to complement lenvatinib for treating anaplastic thyroid cancer. Such combinations may possibly reduce the chances of lenvatinib resistance in thyroid cancer patients.
Highlights
Thyroid cancer remains a significant health problem affecting half a million individuals worldwide
More than 90% of thyroid cancer (TC) are differentiated thyroid carcinomas (DTCs) that arise from follicular cells [papillary thyroid cancer (PTC)-90%, follicular thyroid cancer (FTC)-10%], while medullary thyroid cancer (MTC) and anaplastic thyroid cancer (ATC) account for less than 5% and 2%, respectively, of all thyroid cancers [1]
Tyrosine kinase inhibitor (TKI) demonstrated evaluable clinical responses and stabilization of disease and drugs such as vandetanib and cabozantinib have been approved for the treatment of MTC, while sorafenib and lenvatinib have been approved for DTC that is refractory to radioiodine [7]
Summary
Thyroid cancer remains a significant health problem affecting half a million individuals worldwide. DTC tumor cells often times lose the iodide uptake ability, thereby becoming resistant to radioiodine therapy [3]. In these patients there is a significant worsening of the prognosis. A significant proportion of TC sub-types show aberrations in the receptor tyrosine kinase pathways giving traction to the use of Tyrosine kinase inhibitor (TKI) based therapies for aggressive TC, including DTC, MTC, and ATC [6]. TKIs demonstrated evaluable clinical responses and stabilization of disease and drugs such as vandetanib and cabozantinib have been approved for the treatment of MTC, while sorafenib and lenvatinib have been approved for DTC that is refractory to radioiodine [7]. Lenvatinib is approved for the treatment of radioiodine-refractory differentiated thyroid cancer [9]. We showed that targeted inhibition of XPO1 and PAK4 could sensitize anaplastic thyroid cancer cells to lenvatinib
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