Thyroid cancer is often treated using radioiodine (RAI) therapy, an approach that exploits the thyroid’s relatively unique ability to concentrate iodine. The success of RAI therapy depends on the efficiency of thyroid tumors in trapping and retaining the isotope. Thyroid cancers that harbor oncogenic mutations in activators of MAPK signaling, such as BRAF mutations, have decreased expression of genes that are linked to iodine uptake. They are also associated with worse responses to RAI therapy. Prior studies have shown that transient inhibition of ERK signaling with selumetinib, a MEK inhibitor, can increase iodide uptake in patients with RAI-refractory thyroid cancer. Now, research led by James Fagin at Memorial Sloan Kettering has now demonstrated that CKI, a MEK inhibitor with more sustained activity than selumetinib, leads to greater improvements in the clinical response to RAI therapy in resistant tumors. In mice expressing Braf mutations, sustained suppression of ERK signaling with CKI profoundly increased iodine accumulation in cancer cells. Pretreatment with CKI also enhanced tumor responses to RAI therapy to a greater extent than selumetinib. The accompanying images show pan-cytokeratin-stained thyroid tumors that were treated with RAI only (left), pre-treated with selumetinib (middle), or pre-treated with CKI (right). Note that the thyroid tumors pre-treated with CKI were nearly eliminated by RAI therapy. These results support the concept increasing the potency and duration of ERK inhibition could lead to more effective treatment of RAI-resistant thyroid tumors.
Radioiodide (RAI) therapy of thyroid cancer exploits the relatively selective ability of thyroid cells to transport and accumulate iodide. Iodide uptake requires expression of critical genes that are involved in various steps of thyroid hormone biosynthesis. ERK signaling, which is markedly increased in thyroid cancer cells driven by oncogenic
James Nagarajah, Mina Le, Jeffrey A. Knauf, Giuseppe Ferrandino, Cristina Montero-Conde, Nagavarakishore Pillarsetty, Alexander Bolaender, Christopher Irwin, Gnana Prakasam Krishnamoorthy, Mahesh Saqcena, Steven M. Larson, Alan L. Ho, Venkatraman Seshan, Nobuya Ishii, Nancy Carrasco, Neal Rosen, Wolfgang A. Weber, James A. Fagin