• What is RET?
  • RET in Thyroid Cancer
  • RET M918T
  • Clinical Trials

RET

The RET gene (rearranged during transfection; Takahashi, 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 Shah 2010).

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 Hutchinson 2012).

ret-pathway.png

Figure 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.

Related Pathways

Contributors: Allan V. Espinosa, M.D., Jill Gilbert, M.D.

Suggested Citation: Espinosa, A., J. Gilbert. 2015. RET. My Cancer Genome https://www.padiracinnovation.org/content/disease/thyroid-cancer/ret/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

RET in Thyroid Cancer

RET fusions

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 Nikiforov 2007).

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. 1996).

RET mutations

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.

Table 1. MEN2 Syndromes.
Syndrome MTC Pheochromocytoma Parathyroid hyperplasia Mucosal neuromas
2A + + +
2B + + +
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 2008).

ret-fusions.png

Figure 1.
Schematic of RET fusions found in papillary thyroid cancer.

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Contributors: Allan V. Espinosa, M.D., Jill Gilbert, M.D.

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 M918T Mutations in Thyroid Cancer

 

Properties
Location of mutation Exon 16
Frequency of RET M918T mutation 20–50% sporadic MTC
>90% of MEN2B
Implications for Targeted Therapeutics
Response to non-specific RET inhibitors Improved PFS with vandetanib
Response to specific RET-inhibitors Unknown at this time   
NOTE: MEN2B = multiple endocrine neoplasia type 2B.

The majority of medullary thyroid cancers (MTCs) and approximately 50% of sporadic MTCs harbor a RET M918T mutation. M918T mutations in RET result in an amino acid substitution at position 918, from methionine to threonine.  This mutation alters the substrate specificity of RET kinase, resulting in phosphorylation of alternative intracellular proteins (Santoro et al. 1998).

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 results.


Table 1. Summary of Clinical Trials.
Reference Study Type / Phase Line of Treatment Treatment Agent Mutation Status # Patients in Study Response Rate PFS (months) OS (months unless otherwise indicated)
Lam et al. 2009 Phase II 1st line or greater Sorafenib 9 RET M918T
1 RET C634R
16 non-hereditary MTC 6% 17.9
9 RET M918T 9 non-hereditary MTC 11%
1 RET C634R 1 non-hereditary MTC 0%
NOTE: MTC = medullary thyroid cancer, OS = overall survival, PFS = progression-free survival. ​​
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Contributors: Allan V. Espinosa, M.D., Jill Gilbert, M.D., James Fagin, M.D.

Suggested Citation: Espinosa, A., J. Gilbert, J. Fagin. 2014. RET M918T Mutations in Thyroid Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/thyroid-cancer/ret/128/ (Updated October 20).

Last Updated: October 20, 2014

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