• What is RET?
  • RET in Lung Cancer
  • Clinical Trials


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).


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/lung-cancer/ret/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

RET in Lung Cancer

Approximately 1.3% of lung tumors evaluated have chromosomal changes which lead to RET fusion genes (Ju et al. 2012; Kohno et al. 2012; Takeuchi et al. 2012; Lipson et al. 2012). These gene rearrangements appear to occur almost entirely in adenocarcinoma histology tumors. Histology has not been thoroughly evaluated, but all of the reported lung tumors with RET fusions have been adenocarcinomas (more than 400 lung cancers with histologies other than adenocarcinoma have been tested). Where overlap was evaluated, RET fusions have been shown to occur in tumors without other common driver oncogenes (e.g., EGFR, KRAS, ALK). The three reported fusion genes are CCDC6-RET, KIF5B-RET and TRIM33-RET.

RET fusions were initially identified by RT-PCR, immunohistochemistry, and next-generation sequencing. There is no current standard test for identification of RET fusions in patient samples, but fluorescence in situ hybridization (FISH) or targeted capture/next-generation sequencing are potential methods.

While the functional consequences of RET fusion proteins in lung adenocarcinoma are not fully understood, RET fusions are oncogenic in vitro and in vivo. In in vitro models, RET fusion products may be sensitive to multi-targeted kinase inhibitors such as vandetanib, sorafenib, and sunitinib (Kohno et al. 2012; Lipson et al. 2012).

The clinical significance of RET fusions is not fully understood. There is limited retrospective or prospective data that link presence of RET fusions to response to any particular therapy. However, this is an area of active investigation with prospective clinical trial research currently ongoing (Drilon et al. 2013).

Currently, an inhibitor specific only for RET is not available, but trials of kinase inhibitors with anti-RET activity have been conducted in NSCLC (Table 1). RET testing was not conducted in any of the completed clinical trials listed in table 1; therefore, only limited information is available about the performance of these therapies in patients whose tumors possess RET fusions.

Multi-kinase inhibitors with RET activity include:

  • Vandetanib, which has activity against VEGFR 2/3, EGFR, and RET.
  • Sorafenib, which has activity against VEGFR 1/2, KIT, RET, CRAF, and BRAF.
  • Sunitinib, which has activity against VEGFR 2, KIT, RET, and PDGFRα.
  • Cabozantinib, which has activity against VEGFR 2, KIT, RET, MET, FLT-1/3/4, TIE-2 and AXL.

Table 1. Summary of Completed Clinical Trials with Kinase Inhibitors in NSCLC. 

Reference Treatment Arm Study Phase # pts in study Response Rate PFS (months) OS (months)
Lee et al. 2012 Vandetanib Phase III 617 2.6% 1.9 8.5
Placebo Phase III 307 0.7% 1.8 7.6
Herbst et al. 2010 Docetaxel / vandetanib Phase III 694 17% 4.0 10.6
Docetaxel / placebo Phase III 697 10% 3.2 10.0
Dy et al. 2010 Sorafenib Phase II 25 12% TTF = 2.8 8.8
Gridelli et al. 2011 Sorafenib / erlotinib Phase II 29 10.3% TTF = 12.7 weeks 12.6
Sorafenib / gemcitabine Phase II 31 6.5% TTF = 8.1 weeks 6.55
Spigel et al. 2011 Sorafenib / erlotinib Phase II 111 total, 43 EGFR-WT 8% 3.38 total, 3.38 EGFR-WT 7.62 total, 8.11 EGFR-WT
Erlotinib Phase II 55 total, 24 EGFR-WT 11% 1.94 total, 1.77 EGFR-WT 7.23 total, 4.54 EGFR-WT
Novello et al. 2011 Sunitinib Phase II 64 with brain metastases 1.6% 9.4 weeks 25.1 weeks
Schneider et al. 2011 Sunitinib Phase II 16 0% 2.5
NOTE: TTF = time to treatment failure; WT = wild type.

Contributors: Gregory Riely, M.D., Ph.D.

Suggested Citation: Riely, G. 2012. RET in Lung Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/ret/ (Updated December 13).

Last Updated: December 13, 2012

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