RET (“rearranged during transfection”) is a single-pass transmembrane receptor tyrosine kinase required for normal cellular differentiation, maturation and maintenance. Under normal physiological conditions, RET signaling is activated by binding of a group of soluble proteins of the glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs).1,2 In some heritable and sporadic tumors, however, RET signaling can be constitutively activated in a ligand-independent fashion due to gain of function RET point mutations or genomic rearrangements resulting in oncogenic fusion proteins. This, in turn, results in the activation of the various signaling cascades that lie downstream, including RAS-MAPK, PI3K-AKT, and phospholipase Cγ (PLCγ) pathways. This drives prolonged cell survival and increased proliferation.1, 3, 4. RET fusions have been observed in papillary thyroid cancer, lung adenocarcinoma and colorectal cancer, among other solid tumors. Recently, the RET fusion gene was identified as a new druggable driver gene, sparking an increased interest in identifying RET as a therapeutic target.1, 3
RET Fusion Clinical Prevalence in Lung Cancer
A recent study5 reported 13 out of 936 patients with RET fusion (11 out of 633 patients with adenocarcinoma, 2 out of 24 patients with adenosquamous carcinoma). Of the 13 patients with gene fusions, nine were found to have KIF5B-RET, three had CCDC6-RET and one had NCOA4-RET, a recently discovered gene fusion. Patients with a RET gene fusion manifested a poor differentiation of tumor cells (63.6%; p=0.029 for RET vs. ALK, p=0.007 for RET vs. EGFR), with a tendency to be younger (≤60 years; 72.7%), never-smokers (81.8%), with solid subtype (63.6%), smaller tumor (≤3 cm), and N2 disease (54.4%). The median relapse-free survival was 20.9 months5.
In 2014, Tsuta et al. investigated RET fusions across a sample of 874 patients (1620 adenocarcinomas (ADCs), 203 squamous cell carcinomas (SCCs), 8 large cell carcinomas, and 43 sarcomatoid carcinomas (SACs). In all, 22 cases (1.2%) showed RET rearrangements; all cases were ADC histology. Of the 22 patients, 19 possessed KIF5B–RET gene fusions, whereas three possessed CCDC6–RET gene fusions. The RET-rearranged tumors were significantly more common in younger patients (p=0.038) and tended to occur in patients with no history of smoking (P=0.051),6 thus reinforcing the findings mentioned above.
The clinical prevalence of RET fusions in NSCLC is listed below (adapted from Kohno, 20133).