BACKGROUND: Metastatic thyroid cancers that are refractory to radioiodine 
(iodine-131) are associated with a poor prognosis. In mouse models of thyroid 
cancer, selective mitogen-activated protein kinase (MAPK) pathway antagonists 
increase the expression of the sodium-iodide symporter and uptake of iodine. 
Their effects in humans are not known.
METHODS: We conducted a study to determine whether the MAPK kinase (MEK) 1 and 
MEK2 inhibitor selumetinib (AZD6244, ARRY-142886) could reverse refractoriness 
to radioiodine in patients with metastatic thyroid cancer. After stimulation 
with thyrotropin alfa, dosimetry with iodine-124 positron-emission tomography 
(PET) was performed before and 4 weeks after treatment with selumetinib (75 mg 
twice daily). If the second iodine-124 PET study indicated that a dose of 
iodine-131 of 2000 cGy or more could be delivered to the metastatic lesion or 
lesions, therapeutic radioiodine was administered while the patient was 
receiving selumetinib.
RESULTS: Of 24 patients screened for the study, 20 could be evaluated. The 
median age was 61 years (range, 44 to 77), and 11 patients were men. Nine 
patients had tumors with BRAF mutations, and 5 patients had tumors with 
mutations of NRAS. Selumetinib increased the uptake of iodine-124 in 12 of the 
20 patients (4 of 9 patients with BRAF mutations and 5 of 5 patients with NRAS 
mutations). Eight of these 12 patients reached the dosimetry threshold for 
radioiodine therapy, including all 5 patients with NRAS mutations. Of the 8 
patients treated with radioiodine, 5 had confirmed partial responses and 3 had 
stable disease; all patients had decreases in serum thyroglobulin levels (mean 
reduction, 89%). No toxic effects of grade 3 or higher attributable by the 
investigators to selumetinib were observed. One patient received a diagnosis of 
myelodysplastic syndrome more than 51 weeks after radioiodine treatment, with 
progression to acute leukemia.
CONCLUSIONS: Selumetinib produces clinically meaningful increases in iodine 
uptake and retention in a subgroup of patients with thyroid cancer that is 
refractory to radioiodine; the effectiveness may be greater in patients with 
RAS-mutant disease. (Funded by the American Thyroid Association and others; 
ClinicalTrials.gov number, NCT00970359.).