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
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.
Suggested Citation: Espinosa, A., J. Gilbert. 2015. RET. My Cancer
(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;
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.
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
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
- Sunitinib, which has activity against VEGFR 2, KIT, RET, and
- 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.
||# pts in study
et al. 2012
et al. 2010
||Docetaxel / vandetanib
|Docetaxel / placebo
|Dy et al.
||TTF = 2.8
et al. 2011
||Sorafenib / erlotinib
||TTF = 12.7 weeks
|Sorafenib / gemcitabine
||TTF = 8.1 weeks
et al. 2011
||Sorafenib / erlotinib
||111 total, 43 EGFR-WT
||3.38 total, 3.38 EGFR-WT
||7.62 total, 8.11 EGFR-WT
||55 total, 24 EGFR-WT
||1.94 total, 1.77 EGFR-WT
||7.23 total, 4.54 EGFR-WT
|Novello et al. 2011
||64 with brain metastases
NOTE: TTF = time to treatment failure; WT = wild type
Suggested Citation: Riely, G. 2012. RET in Lung Cancer. My Cancer
(Updated December 13).
Last Updated: December 13, 2012
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