The Evolving Field of Tyrosine Kinase Inhibitors in the Treatment of Endocrine Tumors

Activation of tyrosine kinase receptors (TKRs) and their related pathways has been associated with development of endocrine tumors. Compounds that target and inactivate the kinase function of these receptors, tyrosine kinase inhibitors (TKIs), are now being applied to the treatment of endocrine tumors. Recent clinical trials of TKIs in patients with advanced thyroid cancer, islet cell carcinoma, and carcinoid have shown promising preliminary results. Significant reductions in tumor size have been described in medullary and papillary thyroid carcinoma, although no complete responses have been reported. Case reports have described significant tumor volume reductions of malignant pheochromocytomas and paragangliomas. In addition, these compounds showed an initial tumoricidal or apoptotic response followed by long-term static effects on tumor growth. Despite the promising preliminary results, this class of therapeutic agents has a broad spectrum of adverse effects, mediated by inhibition of kinase activities in normal tissues. These adverse effects will have to be balanced with their benefit in clinical use. New strategies will have to be applied in clinical research to achieve optimal benefits. In this review, we will address the genetic alterations of TKRs, the rationale for utilizing TKIs for endocrine tumors, and current information on tumor and patient responses to specific TKIs. We will also discuss the adverse effects related to TKI treatment and the mechanisms involved. Finally, we will summarize the challenges associated with use of this class of compounds and potential solutions. (Endocrine Reviews 31: 578-599, 2010)