Selumetinib can increase iodine uptake in radioiodine-refractory metastatic thyroid cancer.

  • Major finding: Selumetinib can increase iodine uptake in n radioiodine refractory metastatic thyroid cancer.

  • Mechanism: Constitutive MAPK/ERK activation inhibits expression of thyroid genes that regulate iodine uptake.

  • Impact: MEK inhibition may restore radioiodine efficacy, particularly in NRAS-mutant thyroid cancer.

Radioiodine (iodine-131) is standard treatment for metastatic thyroid cancers, but patients whose tumors do not take up and retain radioiodine have a poor prognosis. Many thyroid cancers have mutations that lead to constitutive activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling, which, in turn, leads to suppression of thyroid genes that mediate the uptake and use of iodine. Preclinical studies have indicated that genetic or pharmacologic inactivation of MAPK/ERK signaling restores iodine uptake in radioiodine-refractory tumors, prompting Ho and colleagues to evaluate whether inhibition of this pathway would have a similar effect in humans. In a pilot study, patients with radioiodine-refractory metastatic thyroid cancer were treated with selumetinib, a smallmolecule inhibitor of MEK, the kinase upstream of MAPK/ERK, and iodine uptake was quantified by iodine-124 position emission tomography (PET) scan. If the PET scan predicted that a therapeutic radiation dose could be delivered, patients would then receive iodine-131 therapy. The primary endpoints were increased iodine-124 uptake and tumor response after iodine-131 treatment. An exploratory endpoint was evaluation of the effect of tumor genotype on the ability of selumetinib to enhance iodine uptake. Among 20 evaluable patients, selumetinib increased iodine-124 uptake in 12 (60%) patients, and 8 (40%) qualified for therapeutic radioiodine. Interestingly, all 5 patients with NRAS mutations exceeded the iodine uptake threshold for radioiodine treatment, and 4 of these patients had confirmed partial responses to radioiodine (the other experienced disease stabilization). Overall, selumetinib safely increased radioiodine uptake in almost all lesions, including bone metastases, and subsequent radioiodine therapy led to durable partial responses or stable disease. These findings support further clinical evaluation of MEK inhibitors to increase radioiodine uptake in patients with radioiodine-refractory metastatic thyroid cancer, particularly those with NRAS mutations.

Ho AL, Grewal RK, Leboeuf R, Sherman EJ, Pfister DG, Deandreis D, et al. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N Engl J Med 2013;368:623–32.

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