RET encodes a transmembrane tyrosine kinase receptor that has three isoforms, long (RET51), intermediate (RET43), and short (RET9), which differ by having and 9 amino acids in the carboxy terminus. RET51 and RET9 are the most commonly expressed isoforms and have different effects on the maturation and development of the kidneys and gut, presumably due to a Grb2 binding site being present in RET51 but not in RET9. Furthermore, RET is a member of the GDNF family receptor complex and is a receptor for the ligands GDNF, artemin (ARTN), neurturin (NRTN), and persephin (PSPN)(23). RET binds these ligands as part of a multi-subunit receptor complex that includes the GDNF Family Receptor alpha (GFR-alpha) proteins, which leads to activation of receptor tyrosine kinases in a variety of signaling pathways including the MAPK, JNK, p38MAPK, and PLC-gamma pathways. Interestingly, there is also controversial data that suggests RET may be a dependence receptor, which can induce apoptosis in certain cell types if it is not bound to a ligand. In metastatic colorectal cancer (CRC) patients. RET fusion kinases represent a novel class of oncogenic driver in CRC and occurred at a 0.2% frequency without concurrent driver mutations, including KRAS, NRAS, BRAF, PIK3CA or other fusion tyrosine kinases.
Luo Y, Tsuchiya KD, Park DI, et al. RET is a potential tumor suppressor gene in colorectal cancer. Oncogene. 2013;32(16):2037-2047.
Le Rolle A-F, Klempner SJ, Garrett CR, et al. Identification and characterization of RET fusions in advanced colorectal cancer. Oncotarget. 2015;6(30):28929-28937.
Subbiah V, Berry J, Roxas M, et al. Systemic and CNS activity of the RET inhibitor vandetanib combined with the mTOR inhibitor everolimus in KIF5B-RET re-arranged Non-Small Cell Lung Cancer with brain metastases. Lung cancer (Amsterdam, Netherlands). 2015;89(1):76-79.