Thyroid cancer (TC) is currently the most common
malignancy of the endocrine system and its incidence has steadily
increased worldwide over the past 20 years (1,2). TC
exhibits considerable heterogeneity and shares typical
histopathological features with other tumors (3). The two varieties of epithelial cells
that constitute the thyroid gland are follicular and parafollicular
cells. Follicular cells convert iodine into T4 and T3, and the
hormones T3 and T4 (tyrosine) regulate metabolism (4). By contrast, parafollicular cells are
epithelial cells that produce calcitonin. Primary TC predominantly
originates from thyroid follicular cells and is classified as an
epithelial tumor, which can be categorized into three primary
pathological types. The most prevalent type is papillary TC (PTC),
followed by follicular TC (FTC), with the most aggressive form
being anaplastic TC (ATC). Furthermore, medullary TC (MTC) arises
from parafollicular cells (5).
Tumorigenesis is mainly driven by somatic mutations
that occur during the initial stages of transformation. According
to various genetic studies on TC, several oncogenes and tumor
suppressor genes have been identified that can be used as
diagnostic markers and therapeutic targets (6–8). For
example, pathogenic loss-of-function mutations in genes responsible
for tumor suppression constitute a common genetic event involved in
TC. Crucial examples include phosphatase and tensin homolog and
tumor protein 53, which are frequently inactivated via such
mutations. These alterations are highly prevalent and
well-characterized events driving the initiation and progression of
TC. The use of targeted therapy in affected patients has become
possible due to the development of tyrosine kinase inhibitors
(TKIs) (9–11). The major driver mutations involved
in TC mainly include B-Raf proto-oncogene (BRAF), RET
(mutations/fusions) and RAS mutations. In addition, gene mutations
related to the VEGFR and PI3K/AKT/mTOR signaling pathways, as well
as mutations in drug resistance-associated genes such as
mesenchymal epithelial transition and neurofibromin 2, are also
closely connected with the regulation of TKI efficacy and the
mechanisms of drug resistance. TKIs function by competing with
adenosine triphosphate (ATP) for binding sites, thus inhibiting
phosphorylation by kinases, and ultimately preventing the signaling
and proliferation of tumor cells (12). Novel and state-of-the-art genetic
testing based on advanced next-generation sequencing has promoted
the development of tumor-targeted therapies, in which the molecular
drivers of tumorigenesis act as the therapeutic targets. Previous
studies (13,14) have compared targeted therapies with
non-targeted agents and immunotherapeutic agents lacking
well-defined molecular targets, including chemotherapeutic drugs
for advanced anaplastic thyroid carcinoma (ATC) and
radioiodine-refractory differentiated thyroid carcinoma (RAIR-DTC),
such as taxanes (paclitaxel, docetaxel), anthracyclines
(doxorubicin), platinum-based agents (cisplatin, carboplatin,
etc.), and PD-1/PD-L1 inhibitors (pembrolizumab, nivolumab). The
results indicate that targeted therapies achieve superior efficacy
and a lower incidence of off-target adverse events. The aim of the
present study was to examine and summarize the role and
organization of the rearranged during transfection (RET)
proto-oncogene, along with its disease-causing mechanisms, in
different variants of TC. In addition, the present revied aimed to
investigate small-molecule inhibitors of tyrosine kinases that
target RET mutations, and present a summary of advances in research
on the management and treatment of TC linked to alterations in the
RET gene.
The RET gene, which is located on chromosome 10q11.2
and encodes a 170 kDa transmembrane receptor tyrosine kinase, was
first discovered by researchers in 1985 (15). Structurally, the RET protein
comprises an extracellular region featuring four cadherin-like
domains (CLD1-4), a calcium-binding site and a cysteine-rich domain
(CRD), a transmembrane region, and an intracellular region
containing the juxtamembrane domain and a bilobed tyrosine kinase
domain (TKD). Under normal physiological conditions, RET activation
is ligand-dependent. The binding of the glial cell line-derived
neurotrophic factor (GDNF) family ligands, along with their
co-receptor GDNF family receptor α, induces RET dimerization. This
dimerization triggers the trans-autophosphorylation of specific
tyrosine residues within the TKD (16–18).
Subsequently, these phosphorylated residues serve as docking sites
for downstream adaptor proteins, initiating crucial signaling
cascades such as the RAS/MAPK and PI3K/AKT pathways, which govern
essential cellular processes, including proliferation,
differentiation and survival (Fig.
1) (19).
The constitutive, ligand-independent activation of
RET, primarily driven by specific mutations, is central to the
pathogenesis of MTC (20–22). These activating mutations occur
either in the germline (hereditary, 95–98%) or somatically
(sporadic, 25–50%) (23–25). The 95–98% refers to germline
mutations accounting for the majority of mutations in hereditary TC
cases, while the 25–50% refers to somatic mutations in all TC cases
(including sporadic ones); these two proportions describe different
mutation subsets and are not mutually exclusive. The global
age-adjusted incidence rate of germline RET mutations is estimated
to be 0.06 cases per 100,000 persons/year, and the corresponding
prevalence is 1.3 cases per 100,000 individuals (26,27).
Germline RET mutations are responsible for virtually
all cases of hereditary MTC, which is categorized as a type of MEN2
syndrome. MEN2 is stratified into two primary clinical subtypes
based on distinct genotype-phenotype associations (28,29).
MEN2A (~95% of cases): This subtype is characterized
by MTC, a high frequency (~50%) of pheochromocytoma and primary
hyperparathyroidism in 20–30% of patients (30). Approximately 95% of MEN2A mutations
(all mutations described in the MEN2A subtype involve cysteine
residues in the extracellular CRD and codon 634 in exon 11) affect
cysteine residues within the extracellular CRD, with codon 634 in
exon 11 being the most prevalent site (85%). The substitution of
cysteine disrupts normal disulfide bonding, leading to aberrant,
ligand-independent receptor dimerization and constitutive kinase
activation (31–33).
MEN2B (~5% of cases): Recognized as the most
aggressive form, MEN2B presents with early-onset, metastatic MTC,
frequent pheochromocytoma, ganglioneuromatosis and marfanoid
habitus (34,35). Over 95% of MEN2B cases are caused
by a specific methionine-to-threonine substitution at codon 918
(M918T) in the TKD activation loop (36). This mutation fundamentally alters
the conformation of the kinase, markedly enhancing its catalytic
activity and enabling robust signaling even in a monomeric or
dimerized state, independent of ligand binding (37,38).
In addition, in <10% of MEN2B cases, A883F mutations or other
combination mutations, such as valine-to-methionine substitution at
codon 804 of RET (V804M), are involved (Fig. 2) (39,40).
These mutations all occur in the RET gene.
Sporadic MTC: Somatic RET mutations are identified
in ~55% of non-hereditary MTC cases (41). The prevalence of these mutations is
associated with tumor burden, markedly rising in advanced or
metastatic disease (42). The
M918T mutation is again the most common somatic variant (~40%),
underscoring its potent oncogenic potential. Other recurrent
somatic mutation sites include codons 611, 618, 620, 630, 634, 768,
883 and 891 (43–47).
RET-activated tumors may arise from chromosomal
rearrangements, which involve the fusion of the RET kinase domain
with various protein partners that possess dimerization domains
(48–50). This phenomenon occurs along with
germline and somatic mutations that activate RET. Previous studies
have proposed that the erroneous repair of DNA double-strand breaks
serves a critical role in the molecular mechanisms that lead to RET
fusion. Specifically, these chromosomal breaks facilitate the
fusion of the 3′ sequence that encodes the RET mRNA kinase domain
with the 5′ sequence that encodes domains responsible for both the
dimerization and localization of an upstream partner gene. This
fusion ultimately results in the production of active RET fusion
proteins, which contribute to tumorigenesis (51–53).
The RET fusion protein can cause cancer through two pathways:
First, by sending a message that promotes the continued
proliferation of cancerous cells due to the ability to send such
messages without a ligand; and secondly, due to the unique
endocytosis process, which prevents RET from being inhibited by
blocking the attachment of ubiquitin to the protein receptor
(54).
The rate at which RET fusion occurs is even higher
in radiation-induced TC. A previous study was performed to analyze
molecular genetic aberrations and associated phenotypes in the
pathological tissues of 191 patients with PTC who were exposed to
radioactive iodine from the Chernobyl reactor as young children.
The results revealed that the frequency of RET gene rearrangements
increased to 62.3% in the first decade following exposure to
radiation. In addition, ELE1/RET (PTC3) rearrangements were
markedly more common than H4/RET (PTC1) rearrangements (75). Note that NCOA4 is the official
symbol for the nuclear receptor coactivator gene involved in this
rearrangement, which is also widely known by the aliases ELE1 and
ARA70. RET/PTC1 is defined as the CCDC6 (formerly H4)-RET gene
fusion, whereas RET/PTC3 corresponds to the NCOA4 (ELE1/ARA70)-RET
gene fusion. An additional investigation of the survivors of the
atomic bombings that took place in Hiroshima and Nagasaki (Japan),
revealed that among 50 patients with PTC who were exposed to
nuclear radiation, 11 (22%) exhibited RET rearrangements, whereas
only 5% of the 21 unexposed patients exhibited the same RET
rearrangements. To the best of our knowledge, this study is the
first to clearly demonstrate a statistically significant positive
association between radiation exposure dose and the incidence rate
of RET/PTC rearrangement in a large-scale human sample (analyzing
249 PTC tumor samples from atomic bomb survivors). Specifically,
the higher the radiation dose received by the survivors, the higher
the proportion of RET/PTC rearrangement in the PTC tumors they
later developed (76).
The specific phosphotyrosine residues on the
activated RET intracellular tail recruit distinct adaptor and
effector proteins, thereby activating multiple downstream signaling
pathways critical for both normal development and oncogenesis
(77–79). The RAS/RAF/MEK/ERK pathway
(80–84) is primarily initiated through
phosphorylated-Y1062 and -Y1096 (these phosphorylated tyrosine
residues are located on the RET protein. Specifically,
phosphorylated-Y1062 and phosphorylated-Y1096 are tyrosine
phosphorylation sites on the intracellular domain of the activated
RET receptor tyrosine kinase), and this pathway is a key driver of
cellular proliferation and differentiation. The PI3K/AKT pathway
(85–87) is a pro-survival pathway that is
activated through several mechanisms, including the recruitment of
SHP2 to phosphorylated-Y687 (phosphorylated-Y687 is also a tyrosine
phosphorylation site on the intracellular domain of the activated
RET receptor tyrosine kinase). The JAK2/STAT3 pathway (88,89)
is activated following the binding of STAT3 to phosphorylated-Y752
and -Y928 (phosphorylated-Y752 and -Y928 are tyrosine
phosphorylation sites of the RET protein), leading to nuclear
translocation and the regulation of target gene expression. The
phospholipase (PLC)γ/protein kinase C pathway (90) is triggered by PLCγ binding to
phosphorylated-Y1015 (phosphorylated-Y1015 is a tyrosine
phosphorylation site on the intracellular domain of the activated
RET receptor tyrosine kinase); this pathway contributes to various
cellular responses.
In cancer, genetic alterations subvert this tightly
regulated system. In MTC, extracellular cysteine mutations (C609,
C611, C618, C620, C630 and C634) cause constitutive dimerization
(91,92), whereas intracellular kinase domain
mutations (for example, M918T and V804M) stabilize the active
conformation, enhance ATP binding or impair autoinhibitory
mechanisms. In PTC, chromosomal rearrangements create RET fusion
genes (93–96). These chimeric proteins, often
lacking the transmembrane domain and fused to dimerization
partners, exhibit ligand-independent, constitutive kinase activity
localized in the cytoplasm. Collectively, these diverse genetic
events lead to the persistent and unregulated activation of
RET-driven oncogenic signaling, fueling tumor initiation, growth
and progression.
Numerous TKI medications have advanced to the stages
of preclinical and clinical development (97–99).
For example, the 2025 National Comprehensive Cancer Network
Guidelines recommendations on TKI inhibitors for TC are as follows
(100): For iodine-refractory PTC
and FTC, both lenvatinib and sorafenib are Category 1
recommendations, with lenvatinib as the preferred first-line option
for locally recurrent/metastatic, progressive radioactive
iodine-refractory PTC and FTC. For MTC, first-line agents include
vandetanib and cabozantinib (Category 1 recommendations). For MTC
with RET mutations, selpercatinib and pralsetinib (highly selective
RET inhibitors) are preferred. For ATC, treatment is mainly
chemotherapy combined with immunotherapy, whereas TKIs may be used
in the setting of positive specific targets. For example,
dabrafenib plus trametinib can be used for tumors with the BRAF
V600E mutation.
The recommendations on TKI inhibitors for TC in the
2025 American Thyroid Association Guidelines (101) include: For TC with RET fusions,
highly selective TKIs, such as selpercatinib (for RET) and
larotrectinib (for neurotrophic tyrosine receptor kinase), are
preferred first-line treatments. These agents demonstrate superior
efficacy and safety compared with conventional multikinase
inhibitors, such as lenvatinib and sorafenib. In the absence of
specific targets, lenvatinib is the first-line choice, and
sorafenib is an alternative. For TC with the BRAF V600E mutation,
dabrafenib plus trametinib may be used as first-line in patients
intolerant to multi-target TKIs; in those who are tolerant, this
combination is reserved for later-line therapy. These kinase
inhibitors are organic compounds with small molecular structures
that interact with the nucleotide-binding site within the kinase
domain, either entirely or in part, and block kinase function
(102,103). Depending on the orientation of
the activation loop, kinases can adopt either an active or an
inactive conformation. A kinase achieves its active state when the
aspartate-phenylalanine-glycine (DFG) motif is located at the
N-terminus of the activation loop; this configuration is referred
to as DFG-in. By contrast, when the DFG motif is found at the
C-terminus of the activation loop, the kinase is considered to be
in an inactive conformation, referred to as DFG-out (104–106). TKIs are divided into two primary
categories based on their preference for DFG-in (Type I) or DFG-out
(Type II) conformations. Type I TKIs function by competing with ATP
at the active site. By contrast, Type II inhibitors promote the
inactive state of kinases by binding both to the ATP-binding pocket
and the nearby allosteric site, which can only be accessed in the
DFG-out conformation (107,108).
Several multikinase inhibitors (MKIs) exhibit
anti-RET activity and are approved for the treatment of TC,
including vandetanib (MTC), cabozantinib (MTC), regorafenib and
sorafenib (differentiated TC). A variety of highly selective RET
inhibitors have been developed. These agents target specific RET
mutations and are associated with lower toxicity, lower required
doses, and lower discontinuation rates compared with MKIs, such as
vandetanib, cabozantinib, regorafenib and sorafenib (109–112).
The LIBRETTO-001 (NCT03157128) trial was an
international, multicenter, open-label, phase I/II trial assessing
the safety and efficacy of selpercatinib (49). A total of 531 patients aged 12
years were enrolled in the study. All of the patients had locally
advanced or metastatic solid tumors of various types. This occurs
with the activation of RET alterations. Of the 531 patients, 162
had RET-altered TC. In the TC subgroup, 55 patients had RET-mutated
medullary TC (MTC) previously treated with cabozantinib and
vandetanib, 88 patients had RET-mutated MTC without prior
cabozantinib or vandetanib treatment, and 19 patients had RET
fusion-positive non-MTC. Notably, these 19 patients had been
previously treated for fusion-positive non-MTC, not for RET-altered
MTC. Based on the findings from the clinical trial, RET-mutant
patients with MTC who were not previously treated with cabozantinib
and vandetanib exhibited an overall response rate (ORR) of 69% and
progression-free survival (PFS) rate of 82% after 1 year. By
contrast, patients with RET-mutant MTC who had not previously
received these treatments had a 73% ORR and a 1-year PFS rate of
92%. For patients with RET fusion-positive non-MTC, the ORR reached
79%, with treatment effectiveness noted across various histological
subtypes and a corresponding 1-year progression-free survival (PFS)
rate. Furthermore, selpercatinib demonstrated overall treatment
effectiveness in all patients with MTC. All patients enrolled in
the LIBRETTO-001 trial, including the 162 patients with RET-altered
TC described in the text, were treated with selpercatinib,
regardless of their previous exposure to MKIs, radioactive iodine,
or the specific type of RET mutation or fusion.
Based on the current research status and clinical
practice, it is proposed that future studies on TKIs targeting RET
alterations should focus on the following aspects: i) The
development of more efficient selective RET inhibitors to overcome
existing resistance mechanisms; ii) the exploration of combinations
of RET inhibitors with other targeted therapies or immunotherapies
to enhance treatment efficacy; and iii) the utilization of
technologies such as liquid biopsy to monitor RET mutations and
resistance in real time, thereby providing a foundation for
personalized treatment.
In conclusion, TC is an increasingly common
endocrine malignancy with genetic drivers, particularly RET
mutations and rearrangements, which serve key roles in MTC and PTC
subtypes, respectively. While targeted RET inhibitors represent a
promising therapeutic advance, future research should prioritize
deeper molecular studies of RET signaling, the interplay between
genetic and environmental risk factors such as radiation, and the
development of improved strategies for early detection and
precision treatment. Advancing these areas will be critical to
enhancing patient outcomes and understanding TC pathogenesis.
Not applicable.
This research was funded by the Anhui Provincial New Era
Education Quality Engineering Project (Graduate Education) (grant
no. 2024qyw/sysfkc017) and the Anhui Medical University Quality
Engineering Project (grant no. 2024×jxm72).
Not applicable.
MW and RW wrote the manuscript. JQ made substantial
contributions to the conception and design of the review's visual
data presentation, created the figures and verified that the visual
content accurately reflected the core research findings and
academic conclusions of the review. JT and QF supervised the
research, revised the manuscript, obtained financial support,
conceptualized the review and performed the literature search. Data
authentication is not applicable. All authors read and approved the
final manuscript.
Not applicable.
Not applicable.
The authors declare that they have no competing
interests.
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