Sustained ERK inhibition maximizes responses of BrafV600E thyroid cancers to radioiodine.
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.
James
J
Nagarajah
Mina
M
Le
Jeffrey A
JA
Knauf
Giuseppe
G
Ferrandino
Cristina
C
Montero-Conde
Nagavarakishore
N
Pillarsetty
Alexander
A
Bolaender
Christopher
C
Irwin
Gnana Prakasam
GP
Krishnamoorthy
Mahesh
M
Saqcena
Steven M
SM
Larson
Alan L
AL
Ho
Venkatraman
V
Seshan
Nobuya
N
Ishii
Nancy
N
Carrasco
Neal
N
Rosen
Wolfgang A
WA
Weber
James A
JA
Fagin
D019943:Amino Acid Substitution; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D007454:Iodides / Q000378:metabolism; D007457:Iodine Radioisotopes / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D020125:Mutation, Missense; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism
C517975:AZD 6244; D001562:Benzimidazoles; D007454:Iodides; D007457:Iodine Radioisotopes; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases
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