RET Fusions in Non-Small Cell Lung Cancer

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).

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.mycancergenome.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
Lee et al. 2012	Placebo	Phase III	307	0.7%	1.8	7.6
Herbst et al. 2010	Docetaxel / vandetanib	Phase III	694	17%	4.0	10.6
Herbst et al. 2010	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
Gridelli et al. 2011	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
Spigel et al. 2011	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.mycancergenome.org/content/disease/lung-cancer/ret/ (Updated December 13).

Last Updated: December 13, 2012

RET Fusions in Non-Small Cell Lung Cancer

Properties
Location of mutation	Chromosomal rearrangements involving the RET gene on 10q11.2
Frequency of RET fusion in lung adenocarcinoma	~1% (Kohno et al. 2012; Takeuchi et al. 2012)
Implications for Targeted Therapeutics
Response to RET TKIs	Unknown at this time^a

Limited information is currently available about the performance of kinase inhibitors with anti-RET activity in patients whose tumors possess RET fusions, but prospective clinical trial research is currently ongoing (Table 1; Drilon et al. 2013).

^a In an initial report from a phase II trial with a RET TKI and with prospective RET testing, three RET fusion positive patients experienced partial responses or disease control when treated with the multi-targeted kinase inhibitor cabozantinib (Table 1; Drilon et al. 2013). In preclinical studies in a Ba/F3 model system expressing a KIF5B-RET fusion, the multi-targeted kinase inhibitor vandetanib inhibited cell proliferation (Takeuchi et al. 2012). In addition, one patient with KIF5B-RET fusion positive lung adenocarcinoma demonstrated a response after treatment with vandetanib (Gautschi et al. 2013).

Table 1. Clinical Trial with a RET TKI and Prospective RET Testing.

Reference	Study Type / Phase	Line of Treatment	Treatment Agent	Mutation Status/Group	# Patients in Study	Response Rate	PFS (months)	OS (months)
Drilon et al. 2013	Phase II	≥ 1st	cabozantinib	RET fusion positive	3	PR - 2 SD - 1	Not reported	Not reported

NOTE: PR = partial response; PFS = progression-free survival; OS = overall survival; SD = stable disease.

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

Suggested Citation: Gautschi, O., G. Riely. 2014. RET Fusions in Non-Small Cell Lung Cancer. My Cancer Genome https://www.mycancergenome.org/content/disease/lung-cancer/ret/127/ (Updated January 17).

Last Updated: January 17, 2014

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