Multikinase inhibitors in the treatment of thyroid cancer: specific role of lenvatinib

Abstract

Thyroid cancers are the most frequent neoplasms of the endocrine system and in the initial stages their prognosis is excellent. However, few therapeutic options are available for advanced or metastatic disease. In the last decade, a better understanding of the molecular events involved in the tumorigenesis of thyroid cancers has led to development of new targeted agents for the management of advanced and refractory disease. Multikinase inhibitors that are able to block pathways involved in the proliferation, invasion, and neoangiogenesis of thyroid cancer have been the most widely studied. After an international effort to identify and recruit sufficient patients, four placebo-controlled studies of multikinase inhibitors have been completed. These trials have led to the approval of the first agents with activity in advanced medullary thyroid cancers, which will probably change the landscape of treatment for iodine-refractory differentiated thyroid cancer in the near future. The purpose of this paper is to review the development of targeted agents for thyroid malignancy, with a special focus on lenvatinib, a multikinase inhibitor.

Keywords: lenvatinib; multikinase inhibitors; targeted therapies; thyroid cancer; tyrosine kinase inhibitors.

Figure 1

Kinase signaling cascade involved in development of thyroid carcinomas and representing the two main pathways, MAPK and PI3K-AKT-mTOR. Abbreviations: RET, rearranged during transfection tyrosine kinase receptor; VEGFR, vascular endothelial growth factor receptor; FGFR, fibroblast growth factor receptor; RAS, rat sarcoma protein; RAF, rapidly accelerated fibrosarcoma kinase; MEK or MAP2K, mitogen-activated protein kinase kinase: ERK or MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositide 3-kinase; PTEN, phosphatase and tensin homolog protein; AKT, protein kinase B; mTOR, mammalian target of rapamycin.

Figure 2

Kinome analysis of lenvatinib. Tyrosine kinase assays were performed by an ELISA and Off-chip Mobility Shift Assay (MSA) by Carna Biosciences, Inc. (Kobe, Japan). A kinome map was made using Cell Signaling Technology (Beverly, MA) methodology. Illustration reproduced courtesy of Cell Signaling Technology, Inc. (www.cellsignal.com).

Figure 3

Proposed mechanism of action of lenvatinib. Abbreviations: RET, rearranged during transfection tyrosine kinase receptor; VEGFR, vascular endothelial growth factor receptor; FGFR, fibroblast growth factor receptor; PDGFR, platelet-derived growth factor receptor.