Sustained ERK inhibition maximizes responses of BrafV600E thyroid cancers to radioiodine
James Nagarajah, … , Wolfgang A. Weber, James A. Fagin
James Nagarajah, … , Wolfgang A. Weber, James A. Fagin
Published September 26, 2016
Citation Information: J Clin Invest. 2016;126(11):4119-4124. https://doi.org/10.1172/JCI89067.
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Brief Report Oncology

Sustained ERK inhibition maximizes responses of BrafV600E thyroid cancers to radioiodine

Abstract

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 BRAF, represses the genetic program that enables iodide transport. Here, we determined that a critical threshold for inhibition of MAPK signaling is required to optimally restore expression of thyroid differentiation genes in thyroid cells and in mice with BrafV600E-induced thyroid cancer. Although the MEK inhibitor selumetinib transiently inhibited ERK signaling, which subsequently rebounded, the MEK inhibitor CKI suppressed ERK signaling in a sustained manner by preventing RAF reactivation. A small increase in ERK inhibition markedly increased the expression of thyroid differentiation genes, increased iodide accumulation in cancer cells, and thereby improved responses to RAI therapy. Only a short exposure to the drug was necessary to obtain a maximal response to RAI. These data suggest that potent inhibition of ERK signaling is required to adequately induce iodide uptake and indicate that this is a promising strategy for the treatment of BRAF-mutant thyroid cancer.

Authors

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

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Figure 2

18F-TFB uptake and kinetic analysis in IEC6 intestinal rat cells and in TPO-Cre LSL-BrafV600E mouse PTCs in response to MAPK inhibitors.

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18F-TFB uptake and kinetic analysis in IEC6 intestinal rat cells and in...
(A) Rates of TFB uptake (2-minute time points) were determined at 140 mM Na+ with various concentrations of TFB. The Km and Vmax were 9.4 ± 1.1 μM and 17 ± 1.1 pmol/μg DNA/2 min, respectively. (B) 18F-TFB uptake in IEC6 cells in the absence or presence of ClO4– or sodium (mean ± SD). (C) Fluorine is not transported via NIS. (D) Time course of 18F-TFB uptake by PET of PTCs of TPO-Cre LSL-BrafV600E mice treated with vehicle (n = 5), AZD6244 (50 mg/kg twice per day, n = 5) or CKI (1.5 mg/kg once per day, n = 5) for 21 days. Graph shows thyroid uptake of 18F-TFB normalized for tumor volume given in % uptake of injected activity (*P = 0.008, CKI vs. AZD6244). Upper row shows representative axial PET thyroid images of mice treated with CKI (magnification ×2.5). Serum TSH was markedly increased in TPO-Cre LSL-BrafV600E compared with wild-type mice, as these animals become hypothyroid upon BrafV600E expression, and were not significantly different in vehicle- vs. CKI/AZD6244-treated animals (not shown). Hence, all 18F-TFB uptake experiments were performed under TSH-stimulated conditions.