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Tyrosine kinase inhibitor-induced thyroid disorders: a review and hypothesis
1Department of Endocrinology and Nephrology, School of Medicine, University of Tokyo, Tokyo, Japan. norimaki-tky@umin.ac.jp
Background:
Thyroid dysfunction is a well-known adverse effect of sunitinib, a drug that targets multiple receptor tyrosine kinases, including vascular endothelial growth factor receptor (VEGFR). As several kinds of tyrosine kinase inhibitors (TKIs) are now available, this has been postulated to be a side effect of the TKIs that target the VEGFR (VEGF-TKIs). However, sunitinib, one of the first-generation TKIs, likely causes thyroid dysfunction more frequently than other TKI classes, leading not only to hypothyroidism, but also to thyrotoxicosis.
Summary:
Based on the reports published to date, including our own studies, we have hypothesized that sunitinib may exert these effects, because it targets a broad spectrum of tyrosine kinases. This not only includes VEGFR2, but also VEGFR1 and the platelet-derived growth factor receptor (PDGFR). This, in turn, may suggest that not only VEGFR2 but also the PDGFR and/or the VEGFR1 play an important role during angiogenesis in the thyroid.
Conclusions:
Our current hypothesis may explain the mechanisms that underlie TKI-induced thyroid disorders. By learning how various kinds of TKIs affect thyroid function, we may elucidate how the angiogenesis in thyroid is regulated both physiologically and pathologically.
Insights
Sunitinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, frequently causes thyroid dysfunction, including hypothyroidism and thyrotoxicosis. This may be due to its broad targeting of tyrosine kinases, impacting thyroid angiogenesis.
Area of Science:
- Oncology
- Endocrinology
- Pharmacology
Background:
- Thyroid dysfunction is a known adverse effect of sunitinib, a multi-targeted receptor tyrosine kinase inhibitor (TKI).
- This side effect is associated with TKIs targeting vascular endothelial growth factor receptor (VEGFR), termed VEGF-TKIs.
- Sunitinib, a first-generation TKI, appears to cause thyroid dysfunction, including hypothyroidism and thyrotoxicosis, more frequently than other TKI classes.
Purpose of the Study:
- To investigate the mechanisms underlying sunitinib-induced thyroid dysfunction.
- To explore the role of sunitinib's broad tyrosine kinase inhibition profile in thyroid disorders.
- To elucidate the regulation of thyroid angiogenesis in physiological and pathological states.
Main Methods:
- Analysis of published reports and own studies on sunitinib's effects on thyroid function.
- Hypothesizing mechanisms based on sunitinib's known kinase targets.
- Review of the role of VEGFR and platelet-derived growth factor receptor (PDGFR) in thyroid angiogenesis.
Main Results:
- Sunitinib targets multiple tyrosine kinases, including VEGFR2, VEGFR1, and PDGFR.
- This broad targeting is hypothesized to be responsible for sunitinib's significant impact on thyroid function.
- Evidence suggests VEGFR2, PDGFR, and/or VEGFR1 play crucial roles in thyroid angiogenesis.
Conclusions:
- The study proposes a hypothesis explaining the mechanisms of TKI-induced thyroid disorders.
- Sunitinib's broad kinase inhibition profile likely contributes to its adverse effects on thyroid function.
- Understanding TKI effects on thyroid function can illuminate the regulation of thyroid angiogenesis.
