Current and Future Role of Tyrosine Kinases Inhibition in Thyroid Cancer: From Biology to Therapy

Abstract

Thyroid cancer represents a heterogenous disease whose incidence has increased in the last decades. Although three main different subtypes have been described, molecular characterization is progressively being included in the diagnostic and therapeutic algorithm of these patients. In fact, thyroid cancer is a landmark in the oncological approach to solid tumors as it harbors key genetic alterations driving tumor progression that have been demonstrated to be potential actionable targets. Within this promising and rapid changing scenario, current efforts are directed to improve tumor characterization for an accurate guidance in the therapeutic management. In this sense, it is strongly recommended to perform tissue genotyping to patients that are going to be considered for systemic therapy in order to select the adequate treatment, according to recent clinical trials data. Overall, the aim of this article is to provide a comprehensive review on the molecular biology of thyroid cancer focusing on the key role of tyrosine kinases. Additionally, from a clinical point of view, we provide a thorough perspective, current and future, in the treatment landscape of this tumor.

Afirma Genomic Sequencing Classifier and Xpression Atlas Molecular Findings in Consecutive Bethesda III-VI Thyroid Nodules

“…Receptor tyrosine kinase fusions are being targeted by small molecule inhibitors to treat late-stage cancers, including advanced thyroid cancer ( 33 ). Inhibitors targeting malignancies with NTRK fusions and RET alterations have received pan- or multicancer US Food and Drug Administration approval ( 34-37 ).…”

“…4 ). The alterations we identified were primarily in RET , a target of several US Food and Drug Administration–approved and investigational therapies ( 33 , 37 , 45 ). Afirma XA does not differentiate germline from somatic alterations.…”

Dynamic Cancer Cell Heterogeneity: Diagnostic and Therapeutic Implications

“…The evolving understanding of disease-specific molecular therapeutic targets has led to the approval of several multi-tyrosine kinase inhibitors (multi-TKIs) for RAI refractory DTC such as Sorafenib (VEGFR/PDGFR and Raf), and Lenvatinib (VEGFR/PDGFR/FGFR/RET), and for MTC such as Vandetanib (EGFR/VEGFR/RET inhibitor) and Cabozantinib (VEGFR/RET) [ 125 , 126 ] ( Figure 5 ). Ongoing clinical trials for multi-TKI inhibitors in different thyroid cancer subtypes were extensively reviewed in 2020 by San Román Gil [ 127 ].…”

Multimodal approach to the treatment of patients with radioiodine refractory differentiated thyroid cancer and metastases to the central nervous system

“…For example, selpercatinib has shown activity in murine models of brain‐implanted tumors that exhibit RET fusion 6 . However, few patients can benefit from these drugs because RET rearrangements have been described in approximately 10% to 20% of patients with papillary thyroid carcinoma and NTRK fusions in 5% to 25% of patients with DTC 7 …”

“… 6 However, few patients can benefit from these drugs because RET rearrangements have been described in approximately 10% to 20% of patients with papillary thyroid carcinoma and NTRK fusions in 5% to 25% of patients with DTC. 7 …”