The RET gene (rearranged during
Ritz, and Cooper 1985), located on chromosome 10, encodes a receptor tyrosine kinase
(RTK) belonging to the RET family of RTKs. This gene plays a crucial role in neural
crest development. Binding of its ligands, the glial cell line derived neurotrophic factor
(GDNF) family of extracellular signaling molecules (Airaksinen,
Titievsky, and Saarma 1999), induces receptor phosphorylation and activation.
Activated RET then phosphorylates its substrates, resulting in activation of
multiple downstream cellular pathways (Figure 1; Phay and
Genomic alterations in RET are found in several different types of cancer.
Activating point mutations in RET
can give rise to the hereditary cancer syndrome, multiple endocrine neoplasia 2 (MEN2; Salvatore et
al. 2000). Somatic point mutations in RET are also associated
with sporadic medullary thyroid cancer (Ciampi and
Nikiforov 2007; Salvatore et al. 2000). Oncogenic
kinase fusions involving the RET gene are found in ~1% of non-small cell lung
cancers (Pao and
1. Schematic of the RET signaling pathway.
RET activation involves binding of glial cell line derived neurotrophic factor
(GDNF)-family ligands as well as interaction with GFR alpha receptors, resulting in
activation of intracellular MAPK and PI3K pathways. The letter "K" within the schema denotes
the tyrosine kinase domain.
Suggested Citation: Espinosa, A., J. Gilbert. 2015. RET. My Cancer
(Updated December 7).
Last Updated: December 7, 2015
RET in Thyroid Cancer
Approximately 10–20% of sporadic papillary thyroid cancers (PTCs) harbor RET fusions.
The prevalence of RET rearrangements is higher in patients with a history of radiation
exposure (50–80%) and in young adults and pediatric populations (40–70%; Ciampi and
Multiple different RET rearrangements have been described in PTCs, but RET/PTC1 (CCDC6-RET;
60–70%; Nikiforov 2008; Nikiforov and
Nikiforova 2011; Nikiforov et al. 1997); RET/PTC2
(PRKAR1A-RET; 5%; Nifikorov et al. 1997), and RET/PTC3
(NCOA4-RET; 20–30%; Mochizuki et al. 2010) account for the
vast majority of cases. These oncogenic rearrangements consist of various 5’ partners
fused to the kinase domain of RET, leading
to constitutive activation of the RET kinase
(Pierotti et al.
Both germline and somatic mutations can
occur in RET. Virtually all patients with multiple endocrine neoplasia 2 (MEN 2) harbor
germline mutations in RET. MEN 2 is
divided into three distinct syndromes: MEN 2A, MEN 2B, and Familial Medullary Thyroid Cancer
(see Table 1). Somatic mutations are
associated with as many as 50% of sporadic medullary thyroid cancers.
|Familial Medullary Thyroid cancer
NOTE: MTC = medullary thyroid cancer.
At least 19 different codons in 7 exons of
RET have been found to be mutated. However, the majority of mutations in most familial and sporadic MTCs involve
codons 634 and 918 (Nikiforov
1. Schematic of RET fusions found in papillary thyroid cancer.
Suggested Citation: Espinosa, A., J. Gilbert. 2015. RET in Thyroid Cancer. My
Cancer Genome https://www.padiracinnovation.org/content/disease/thyroid-cancer/ret/
(Updated June 18).
Last Updated: June 18, 2015
RET Fusions in Thyroid Cancer
|Location of mutation
||chromosomal rearrangements involving the RET gene
|Frequency of RET fusion
||10–20% of sporadic PTCs
|Implications for Targeted Therapeutics
|Response to non-specific RET TKIs
||Improved PFS with vandetanib
|Response to specific RET TKIs
||Unknown at this time
Currently, an inhibitor specific only for RET is not available, but trials of kinase inhibitors with anti-RET activity
have been conducted in advanced iodine-refractory DTC (differentiated thyroid cancer) and in
medullary thyroid cancer (MTC; Table 1).
Sorafenib is a multi-targeted kinase inhibitor
with activity against VEGFR 1 and 2, KIT, RET and wild type
BRAF. This agent demonstrated partial response rates of 23–56% (DTC) and 6% (MTC) in
phase II trials. Progression free survivals ranged from 14 to 18.4 months (DTC) and 17.9
months (MTC) (Gupta-Abramson
et al. 2008; Kloos et al. 2009; Lam et al. 2010).
Sunitinib is a multi-targeted kinase inhibitor
with activity against VEGFR 2, KIT, RET, and PDGFRα. This agent demonstrated a
response rate of 33% and median time to progression of 12.8 months in a phase II trial of
patients with iodine refractory DTC and in MTC (Carr et al. 2010).
Vandetanib is a multi-targeted kinase inhibitor
with activity against VEGFR 2 and 3, EGFR, and RET. In a phase II trial of advanced MTC,
this agent demonstrated a response rate of 20% and a disease control rate of 73%, with a
median progression free survival of 27.9 months (Wells et al. 2010).
A phase III multicenter randomized trial that compared vandetanib versus placebo in patients
with locally advanced and metastatic MTC showed an improved progression free survival with a
hazard ratio of 0.46 (confidence intervals 0.3–0.69). However, no improvement in
overall survival was observed (Wells et
al. 2012; Sherman 2011). Vandetanib is FDA approved
for the treatment of adult patients with metastatic medullary thyroid cancer (MTC) who are
ineligible for surgery and who have progressive or symptomatic disease.
Other multi-kinase inhibitors, such as XL184 and motesanib, have also shown promising
Summary of Clinical Trials.
||Study Type / Phase
||Line of Treatment
||# Patients in Study
||OS (months unless otherwise indicated)
|Lam et al. 2009
||1st line or greater
||9 RET M918T
1 RET C634R
|16 non-hereditary MTC
|9 RET M918T
||9 non-hereditary MTC
|1 RET C634R
||1 non-hereditary MTC
NOTE: MTC = medullary thyroid cancer, OS = overall survival, PFS = progression-free
Suggested Citation: Espinosa, A., J. Gilbert, J. Fagin. 2014. RET Fusions in
Thyroid Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/thyroid-cancer/ret/127/
(Updated October 20).
Last Updated: October 20, 2014
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