RET, the rearranged during transfection proto-oncogene, encodes a receptor tyrosine kinase [4]. Physiologically, RET receptors are activated by glial cell line-derived neurotrophic factor (GDNF) family ligands binding to the coreceptor GDNF family receptor α (GFRα), playing crucial roles in the development of the enteric nervous system, kidneys, urinary tract, and self-renewal of spermatogonial stem cells. Another ligand, growth differentiation factor-15 (GDF15), can also bind to GFRα-like and activate RET, regulating body weight [4].

RET alterations, including point mutations and gene fusions, are found in diverse cancers such as papillary thyroid carcinoma (PTC), non-small cell lung cancer (NSCLC), multiple endocrine neoplasia 2 (MEN2), and medullary thyroid carcinoma. RET fusions, like CDCC6-RET and NCOA4-RET in PTC and KIF5B-RET in NSCLC, result in abnormal expression and activation of the oncogenic kinase [1,2]. Inhibiting RET kinase has been a therapeutic approach. Multikinase inhibitors (MKIs) like sunitinib, sorafenib, etc., target RET among other kinases, but have issues with high-grade adverse events and resistance. Selective RET inhibitors, selpercatinib (LOXO-292) and pralsetinib (BLU-667), have shown high response rates in clinical trials across multiple RET-altered cancers, though acquired resistance mutations like RET G810X can develop [1,2,3].

In conclusion, RET is essential for normal development and is involved in key metabolic and self-renewal processes. In disease, RET alterations, especially in cancers, have made it a target for therapy. The development of selective RET inhibitors based on understanding RET's role from research, though facing resistance challenges, offers new hope for treating RET-driven cancers.

References:

1. Li, Andrew Y, McCusker, Michael G, Russo, Alessandro, Adamo, Vincenzo, Rolfo, Christian. 2019. RET fusions in solid tumors. In Cancer treatment reviews, 81, 101911. doi:10.1016/j.ctrv.2019.101911. https://pubmed.ncbi.nlm.nih.gov/31715421/

2. Liu, Xuan, Hu, Xueqing, Shen, Tao, Mooers, Blaine H M, Wu, Jie. 2020. RET kinase alterations in targeted cancer therapy. In Cancer drug resistance (Alhambra, Calif.), 3, 472-481. doi:10.20517/cdr.2020.15. https://pubmed.ncbi.nlm.nih.gov/35582449/

3. Desilets, Antoine, Repetto, Matteo, Yang, Soo-Ryum, Sherman, Eric J, Drilon, Alexander. 2023. RET-Altered Cancers-A Tumor-Agnostic Review of Biology, Diagnosis and Targeted Therapy Activity. In Cancers, 15, . doi:10.3390/cancers15164146. https://pubmed.ncbi.nlm.nih.gov/37627175/

4. Takahashi, Masahide. . RET receptor signaling: Function in development, metabolic disease, and cancer. In Proceedings of the Japan Academy. Series B, Physical and biological sciences, 98, 112-125. doi:10.2183/pjab.98.008. https://pubmed.ncbi.nlm.nih.gov/35283407/