Published OnlineFirst November 24, 2009; DOI: 10.1158/1078-0432.

CCR-08-2742

Molecular Pathways

Targeting the RET Pathway in Thyroid Cancer

Samuel A. Wells, Jr.1 and Massimo Santoro2

Abstract

The RET (rearranged during transfection) protooncogene encodes a single pass transmembrane receptor that is expressed in cells derived from the neural crest and the urogenital tract. As part of a cell-surface complex, RET binds glial derived neurotrophic
factor (GDNF) ligands in conjunction with GDNF-family co-receptors (GFR).
Ligand-induced activation induces dimerization and tyrosine phosphorylation of the
RET receptor with downstream activation of several signal transduction pathways. Activating germline RET mutations play a central role in the development of the multiple
endocrine neoplasia (MEN) syndromes MEN2A, MEN2B, and familial medullary thyroid
carcinoma (FMTC) and also in the development of the congenital abnormality Hirschsprung's disease. Approximately 50% of patients with sporadic MTC have somatic RET
mutations, and a significant portion of papillary thyroid carcinomas result from chromosomal inversions or translocations, which activate RET (RET/PTC oncogenes). The
RET protooncogene has a significant place in cancer prevention and treatment. Timely
thyroidectomy in kindred members who have inherited a mutated RET allele, characteristic of MEN2A, MEN2B, or FMTC, can prevent MTC, the most common cause of
death in these syndromes. Also, recently developed molecular therapeutics that target
the RET pathway have shown activity in clinical trials of patients with advanced MTC, a
disease for which there has been no effective therapy. (Clin Cancer Res 2009;15(23):
711923)

Background
Medullary thyroid carcinomas (MTC) are derived from the
neural crest C cells, not from the follicular cells, as are papillary
thyroid carcinoma (PTC) and follicular thyroid carcinoma
(FTC). The malignancy presents either sporadically (75% of
cases) or in a hereditary pattern (25% of cases) as either multiple endocrine neoplasia (MEN) type 2A, MEN2B, or familial
MTC (FMTC). Clinically, the hereditary forms of MTC are characterized by complete penetrance but variable expressivity, such
that the MTC occurs in virtually all patients, however, only 50%
of patients with MEN2A and MEN2B develop pheochromocytomas, and 30% of patients with MEN2A develop parathyroid
hyperplasia. Patients with FMTC only develop MTC (1).
The RET (rearranged during transfection) protooncogene
(Fig. 1) is located in the pericentromeric region of chromosome
10q11.2 and spans 21 exons (2). RET encodes a receptor tyro-

Authors' Affiliations: 1 Center for Cancer Research, National Cancer

Institute, National Institutes of Health, Bethesda, Maryland and
2
Dipartimento di Biologia e Patologia, Cellulare e Molecolare, Universita'
di Napoli Federico II, Naples, Italy
Received 6/19/09; revised 8/27/09; accepted 8/27/09; published OnlineFirst
11/24/09.
Requests for reprints: Samuel A. Wells, Jr., Center for Cancer Research,
National Cancer Institute, National Institutes of Health, Building 10, Room
3-2571, 9000 Rockville Pike, Bethesda, MD 20892. Phone: 301-435-7864;
Fax: 301-496-9020; E-mail: wellss@mail.nih.gov.
F 2009 American Association for Cancer Research.
doi:10.1158/1078-0432.CCR-08-2742

www.aacrjournals.org

sine kinase, which is expressed in neuroendocrine cells (including thyroid C cells and adrenal medullary cells), neural cells
(including parasympathetic and sympathetic ganglion cells),
urogenital tract cells, and testis germ cells. RET protein is structured
with an extracellular portion (which contains four cadherinlike repeats, a calcium binding site, and a cysteine-rich region),
a transmembrane portion, and an intracellular portion, which
contains two tyrosine kinase subdomains (TK1 and TK2) that
are involved in the activation of several intracellular signal transduction pathways. Alternate splicing of RET produces three isoforms with either 9, 43, or 51 amino acids at the C terminus,
referred to as RET9, RET43, or RET51 (3).
A tripartite cell-surface complex is necessary for RET signaling.
One of four glial derived neurotrophic factor (GDNF) family ligands (GFL), GDNF, neurturin, artemin, or persephin, binds RET
in conjunction with one of four glycosylphosphatidylinositolanchored co-receptors, designated GDNF-family receptors
(GFR): GFR1, GFR2, GFR3, and GFR4 (48). GDNF primarily associates with GFR1, whereas neurturin, artemin, and
persephin preferentially bind GFR2, GFR3, or GFR4, respectively. Mice lacking GFR4 have defects in calcitonin production,
highlighting a role for the persephin receptor in regulating thyroid
C cell function (9). Ligand stimulation leads to activation of the
RET receptor with dimerization and subsequent autophosphorylation of intracellular tyrosine residues, which serve as docking sites
for various adaptor proteins (10, 11).
RET is a versatile kinase, which is capable of directly phosphorylating multiple downstream targets (Fig. 1). Y905 is a
binding site for Grb7/10 adaptors, however, the function of

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Molecular Pathways

Fig. 1. The RET structure and signaling

network. The structure of the RET
protein and the signaling network,
showing docking sites and targets.
ART, artemin; NTN, neurturin; PSP,
persephin; Ca++, calcium ion.

the adaptors has not been completely elucidated. The transcription factor STAT3 is activated through phosphorylation of Y752
and Y928. Janus kinases (JAK), c-Src, and the Ras/ERK pathway
have also been involved in STAT3 activation by different RETderived oncoproteins (12). Phosphorylated Y981 is the major
binding site for Src, which is essential for neuronal survival.
Src is also necessary for RET signaling through focal adhesion
kinase (FAK), an important mediator of tumor cell migration
and metastases (13). RET 981 is also involved in AKT activation
(14). RET phospholipase C interacts with activated RET by
binding Y1015, thereby activating protein kinase C enzymes,

Clin Cancer Res 2009;15(23) December 1, 2009

which in turn are key regulators of receptor tyrosine kinases

(15). Mice lacking RET 1015 have defects in kidney development (16). Nonphosphotyrosine dependent mechanisms are
involved in RET signaling as well. Phosphorylation of RET
S697 is critical for activation of the RAC1/JUN NH(2)-terminal
kinase (JNK) pathway and mice lacking S697 exhibit enteric
nervous system defects (17). The C-tail of RET9 but not
RET51 binds the PDZ-containing scaffold protein Shank3, contributing to sustained ERK and PI3K signaling (18).
Finally, Y1062 is a highly important multidocking binding
site for such proteins as DOK1/4/5, Enigma, FRS2, IRS1/2,

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Targeting the RET Pathway in Thyroid Cancer

Shc, and ShcC. Phosphorylation of 1062 also results in activation of major intracellular pathways, including RAS/ERK, PI3K/
AKT, nuclear factor B (NFB), and JNK (10, 12, 1925). The
well-characterized RAS > RAF > MEK > ERK pathway plays an
important role in thyroid carcinoma as RAS mutations are
found in FTC and in the follicular variant of PTC. BRAF mutations are found in PTC and anaplastic thyroid carcinoma. The
role of RAS mutations in MTC is controversial (26, 27). The
PI3K > AKT pathway plays a key role in RET signaling, however,
to date there has been little genetic analysis of this pathway
in MTC.
Recently, the biochemical characterization and structure of
the human RET tyrosine kinase domain was reported to
show that both the phosphorylated and nonphosphorylated
forms adopt the same active kinase conformation necessary
to bind ATP and substrate and have a pre-organized activation loop conformation that is independent of phosphorylation status (28).

Clinical-Translational Advances
In 1990 Grieco and associates reported that some PTCs were
caused by a transforming oncogene, resulting from the rearrangement of a heterologous amino terminal sequence to the
tyrosine kinase domain of RET (29). It was subsequently shown
that this hybrid oncogene, termed RET/PTC, was present in approximately 5 to 40% of PTCs and resulted from double-stranded
DNA breaks with erroneous rearrangements involving the
C-terminal portion of RET and the promoter and coding region
of the N terminus of a constitutively expressed unrelated gene
from chromosome 10 or a different chromosome (30). These
fusion oncogenes were found to be particularly common in
patients previously exposed to radiation, such as the children
living near the Chernobyl nuclear accident, in patients exposed
to external irradiation, or in victims of the atomic bomb explosion in Japan during World War II (3133). Spatial proximity
of RET and fusion partner's loci involved in the recombination
in interphase chromatin has been shown as a mechanism of
radiation-induced recombination (34). Most PTCs, however,
are caused by an activating mutation in the B isoform of Raf
kinase, BRAFV600E (35). PTCs caused by BRAF mutations, compared with those resulting from RET/PTC translocations, are
larger, have a higher incidence of local tissue invasion and lymph
node metastases, and have a poorer clinical prognosis (36).
In 1993 and 1994 it was shown that point mutations in the
RET protooncogene cause MEN2A, MEN2B, and FMTC (see
COSMIC catalog 3 and the MEN2 database; 4 refs. 37, 38).
MEN2A is associated with mutations involving the extracellular
cysteine codons 609, 611, 618, 620 (exon 10) 630, or 634 (exon 11). The mutations associated with FMTC involve a broad
range of codons including some associated with MEN2A, particularly, 609, 618, and 620, as well as others: 768, 790, and
791 (exon 13), 804 and 844 (exon 14), or 891 (exon 15). In
95% of patients with MEN2B there is a point mutation in codon 918 (exon 16, Met918Thr) within the intracellular domain

3
4

http://www.sanger.ac.uk
http://www.arup.utah.edu/database/MEN2/MEN2_welcome.php

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of RET (39). A few patients with MEN2B have a mutation in

codon 883 (exon 15; ref. 40). Single MEN2B patients with double RET mutations Val804Met + Ser904Cys and Val804Met +
Tyr806Cys have been reported (41, 42). In MEN2A and FMTC
the RET mutations lead to a ligand-independent homodimerization and constitutive kinase activity such that RET becomes a
dominant oncogene. In MEN2B RET mutations activate the RET
receptor in its monomeric state, leading to phosphorylation of
Y1062 and other tyrosines, and also causing a change in substrate specificity (9).
It is likely that RET does not act alone in the genesis of hereditary MTC, and studies of MTC tissues and cell lines from
patients with MEN2A have shown evidence of a second hit as
evidenced by trisomy 10 with duplication of the mutant RET
allele, loss of the wild-type RET allele, and a tandem duplication event with amplification of mutant RET (43). Almost certainly additional genetic defects, such as chromosomal
deletions and amplifications will be shown in future studies.
Probably, given the young age at presentation, fewer additional
genetic alterations occur in MTC in patients with the germline
MEN2B mutation. A recent array CGH study unveiled many
gene copy number alterations in MTC patients (44). Approximately 50% of patients with sporadic MTC have somatic mutations in RET codon 918 and these tumors seem to be more
aggressive clinically compared with tumors lacking the somatic
RET mutation (45).
In patients with MEN2A, MEN2B, and FMTC there is a correlation between genotype and phenotype, both in the clinical
expression of the disease spectrum and the clinical aggressiveness of MTC. Whereas, virtually all patients develop MTC,
pheochromocytomas develop in approximately 50% of patients with MEN2A and MEN2B. In MEN2A they occur most
often in patients with RET mutations in codon 634 and less frequently in patients with mutations in codons 618, 620, or 791.
Hyperparathyroidism occurs only in patients with MEN2A who
have mutations in codons 618, 630, 634, or 791. Considering
the age of onset and clinical aggressiveness of MTC, patients are
classified as being at highest risk, higher risk, or high risk. Patients with MEN2B, who have mutations in codons 918 or 883
represent the highest risk group, whereas patients with mutations in codons 634, 630, 609, 611, 618, and 620 are in the
higher risk group. The high risk group includes patients with
mutations in codon 768, 790, 791, 804, and 891 (46).
Rarely, the dermatologic disorder cutaneous lichen amyloidosis and the congenital disorder Hirschsprung's disease (HSCR;
aganglionic megacolon) may occur in association with MEN2A
(46, 47). Hirschsprung's disease, the most common cause of intestinal obstruction in the newborn, is characterized by the absence of enteric ganglia in variable segments of intestine. A RET
mutation has been identified in only 50% of familial and 15 to
20% of sporadic cases of HSCR (48, 49). More than 100 different RET mutations have been described, and, in contrast to mutations in MEN2A, MEN2B, FMTC, and sporadic MTC, which
are virtually all missense mutations, they include microdeletions, insertions, nonsense and missense, and splicing mutations. In some cases the entire RET gene is deleted (50). The
RET mutations associated with MEN2A, MEN2B, and FMTC
syndromes are generally gain-of-function mutations, whereas
the RET mutations occurring in HSCR are loss-of-function mutations, most likely associated with a haploinsufficiency or
dominant negative effect.

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Molecular Pathways

Rarely, patients with MEN2A who have RET mutations in codons 609, 611, 618, or 620 (exon 10) develop HSCR (47).
Functional studies have shown that cell surface expression of
these RET mutants is lower than that associated with other
RET mutations, such as 634 (51). Thus, these four mutations
lead to constitutive activation of RET and continued proliferation of C cells on one hand, whereas on the other, they result in
a marked reduction of RET expression at the cell membrane,
and a resultant apoptosis of enteric neurons.
There is no better example of the translation of genetic information into clinical practice than that provided by detection of
RET mutations in patients with hereditary MTC. Shortly, after
the discovery that MEN2A, MEN2B, and FMTC were caused
by mutations in the RET protooncogene, it became clear that
family members who carried a mutated RET allele could be detected by direct DNA analysis. Knowing that the MTC was the
most common cause of death in patients with these syndromes
and that the thyroid gland was an expendable organ whose
function could be easily replaced by the oral administration
of the drug thyroxin, several centers initiated screening programs in MEN type 2 families to identify kindred members with
RET mutations. The thyroid gland can be removed safely and
the operation is curative if done at a young age, before the
MTC develops or is still confined to the thyroid gland (52,
53). Although, there is general agreement that prophylactic thyroidectomy is indicated in members of families with hereditary
MTC, the timing of thyroidectomy depends on the site of the
RET codon mutation. Thyroidectomy is advised at a very early
age (even in the first months of life) in patients at highest risk
(mutations in codon 918 or 883), at 5 years of age in patients at
higher risk (mutations in codons 611, 618, 620, and 634), and
between 5 and 10 years of age in patients at high risk (mutations in codons 609, 768, 790, 791, 804, or 891; refs. 54, 55).
The finding that the molecular targeted therapeutic (MTT)
STI571 (imatinib mesylate, Novartis AG) induced remissions
in patients with chronic myelogenous leukemia has had a
profound effect on clinical medicine and has changed the landscape of cancer therapy (56). The anilinoquinazoline vandetanib (AstraZeneca Limited) selectively inhibits the kinase insert

domain-containing receptor [KDR/vascular endothelial growth

factor receptor (VEGFR2) tyrosine kinase activity (IC 50
40 nM)]. The compound also has activity against VEFGR3;
IC50 = 110 nM and epidermal growth factor receptor (EGFR/
HER1; IC50 = 500 nM; ref. 57). In 2002 Carlomagno and associates showed that ZD6474 is a potent inhibitor (IC50 = 100 nM)
of RET oncoproteins. These investigators also found that
ZD6474 has a marked inhibitory effect on the growth of thyroid cancer cell lines with spontaneous RET/PTC rearrangements and also the growth of NIH-RET/PTC xenografts (58).
Phase I studies showed that ZD6474 administration is associated with minimal toxicity and subsequent phase II clinical trials
showed that ZD6474 has activity in patients with locally advanced or metastatic hereditary MTC. Approximately 20% of
patients experienced a partial remission, as shown by RECIST
(response evaluation criteria in solid tumors) criteria and another 60% experienced stable disease for a disease control rate
of 80% (59). Following treatment, there was reduction in serum levels of calcitonin and carcinoembryonic antigen, tumor
markers secreted by the MTC cells. Subsequently, it was shown
that vandetanib induced confirmed partial remissions in 85%
of children with advanced MEN2B (60). Phase II clinical trials
of other MTTs have also shown activity in patients with advanced MTC (61, 62).
The molecular analysis of tumor tissue in patients whose
chronic myeloid leukemia recurred following initial treatment
with imatinib mesylate was fundamental to the design of successful rescue therapy and to the development of combinatorial
regimens to prevent disease recurrence following primary treatment (63). Unfortunately, there has been a paucity of such
studies in clinical trials of MTTs in advanced thyroid cancer, primarily because tissue acquisition has been infrequent or nonexistent. This issue must be corrected if we are to improve the
treatment of patients with this disease.

Disclosure of Potential Conflicts of Interest

S.A. Wells, Jr., consultant, AstraZeneca. M. Santoro, commercial
research grant, AstraZeneca.

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Clin Cancer Res 2009;15(23) December 1, 2009

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Published OnlineFirst November 24, 2009; DOI: 10.1158/1078-0432.CCR-08-2742

Targeting the RET Pathway in Thyroid Cancer

Samuel A. Wells, Jr. and Massimo Santoro
Clin Cancer Res 2009;15:7119-7123. Published OnlineFirst November 24, 2009.

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