Targeted Therapy for Advanced Thyroid Cancer: Kinase Inhibitors and Beyond

Abstract

The treatment of advanced thyroid cancer has undergone rapid evolution in the last decade, with multiple kinase inhibitor drug approvals for each subtype of thyroid cancer and a number of other commercially available drugs that have been studied for this indication. Although most of the US Food and Drug Administration (FDA)-approved drugs are antiangiogenic multikinase inhibitors-vandetanib, cabozantinib, sorafenib, lenvatinib-there are two FDA indications that are mutation specific-dabrafenib/trametinib for BRAF-mutated anaplastic thyroid cancer and larotrectinib for NTRK-fusion thyroid cancer. Furthermore, other mutation-specific drugs, immunotherapies, and novel strategies for advanced thyroid cancer are under investigation. Understanding the molecular basis of thyroid cancer, the drugs of interest for treatment of advanced thyroid cancer, and how these drugs can be administered safely and in the appropriate clinical scenario are the topics of this review.

Figure 1.

Upregulation of the MAPK pathway in tumor cells leads to proliferation and progression of thyroid cancer. Increased signaling along the MAPK pathway is caused by genetic mutations occurring in the pathway (such as those of BRAF and RAS), activation of receptor tyrosine kinases due to mutations (such as those of RET), overactivation of these kinases by growth factors, and fusion receptor tyrosine kinases (such as RET and NTRK fusions). Shown are several drugs capable of targeting upstream receptor tyrosine kinases, specific mutations, and genetic rearrangements that are either FDA approved for thyroid cancer or of interest in treating this disease. Furthermore, constitutively activated MEK (due to BRAF V600E or RAS mutations) leads to decreased expression of thyroid-specific genes, particularly NIS, resulting in RAI refractoriness. Inhibition of BRAF or MEK reverses this effect and restores RAI avidity. Furthermore, complex interplay between the immune system and cancer cells exists, including inhibitory and stimulatory interactions. Expression of inhibitory ligands such as programmed death-ligand 1 (PD-L1) on tumor cells effectively turns off the T cells, leading to evasion of the immune response. Blockade of such signals with checkpoint inhibitor drugs is depicted in the figure. Several immunotherapeutic drugs are approved for several solid tumors but not thyroid cancer. CTLA-4, cytotoxic T-lymphocyte–associated protein 4; FGFR, fibroblast growth factor receptor; MHC, major histocompatibility complex; NIS, sodium iodide symporter; PD-1, programmed cell death protein 1; PI3K, phosphoinositide 3-kinase; TCR, T-cell receptor.

Figure 2.

Management of locally advanced and/or metastatic differentiated cancer or MTC and the criteria for initiation of systemic therapy with kinase inhibitors. RANKL, receptor activator of nuclear factor-кB. [Reprinted by permission from Springer Nature, Hormones & Cancer; Cabanillas ME, Patel A, Danysh BP, Dadu R, Kopetz S, Falchook G. BRAF inhibitors: experience in thyroid cancer and general review of toxicity. Horm Cancer. 2015;6:21–36.]