The unique signature of tyrosine kinase inhibitor-induced hypothyroidism

Tyrosine kinase inhibitors (TKIs) are anti-cancer agents that inhibit the activity of oncogenic protein kinases. Thyroid hormone abnormalities are common during treatment with TKIs, typically manifesting as increased serum thyroid stimulating hormone concentrations and reduced tri-iodothyronine (T₃) to thyroxine (T₄) ratio, both in patients with an intact thyroid gland and those with hypothyroidism receiving thyroid hormone treatment. Studies have highlighted the effect of TKIs on peripheral thyroid hormone metabolism, particularly through interference with the activity of deiodinases in healthy tissues. These enzymes are targets of TKIs, and their altered function might contribute considerably to the changes in circulating thyroid hormone concentrations. Although such alterations can affect the tolerability to TKI treatment, TKI-induced hypothyroidism has been associated with improved survival outcomes. Several advanced malignancies show overexpression of type 2 deiodinase, suggesting that inhibition of this enzyme in tumour tissue might contribute to the anti-tumour effects of TKIs. This Review summarises advances in the understanding of TKI-induced disruption of thyroid hormone homoeostasis, and discusses clinical strategies for managing hypothyroidism in this setting.