RET

RET is a proto oncogene located on chromosome 10. The gene encodes a transmembrane receptor of protein tyrosine protein kinase family and plays an important role in the development of nervous system and neural crest derived. Ligands such as GDNF (glial cell line derived neurotrophic factor) or other related proteins bind to RET encoded receptors to stimulate receptor dimerization and activate downstream signaling pathways, which play a role in cell differentiation, growth, migration and survival. KIT can be activated by genome rearrangement and point mutation. KIT mutations are associated with Hirschsprung disease and central cord syndrome and have been found in patients with renal hypoplasia. Other RET related diseases include thyroid cancer, germline medullary thyroid cancer and multiple endocrine tumors type IIa. The related pathways include cancer center carbon metabolism and RET signaling pathway. GO annotations associated with KIT include calcium binding and protein kinase activity (PMID: 24561444, PMID: 19487296, PMID: 25810047, PMID: 29142004).

The frequency of RET gene fusion in non-small cell lung cancer (NSCLC) is about 1%-2%, and RET gene fusion is found in about 5%-40% of papillary thyroid carcinoma (PTC). The FDA has approved the following drugs for RET-targeted therapy in other tumors: Cabozantinib - Kidney cancer & Medullary thyroid cancer (liver cancer approved by FDA, lung cancer stage I-II); Lenvatinib - Thyroid & Kidney & Liver cancer (Phase II lung cancer); Regorafenib - Colorectal cancer & Gastrointestinal stromal Tumor & Liver Cancer; Sorafenib (RAF inhibitor) - Liver cancer & Kidney Cancer & Thyroid Cancer; Sunitinib- Gastrointestinal stromal tumor & Pancreatic cancer & Kidney Cancer; Vandetanib medullary thyroid carcinoma (non-small cell lung cancer). The CFDA approved the following drugs for RET targeted therapy in other tumors: Apatinib - Gastric cancer (phase III non-small cell lung cancer); In addition, the new drugs under clinical development have shown good therapeutic effects on NSCLC: The drug under development, PU-667 (phase I clinical trial) - NSCLC & thyroid medullary & papillary thyroid cancer, has an effective rate of up to 46% and a control rate of over 90% for patients with RET gene fusion or mutation. Loxo-292 - Non-small Cell Lung Cancer & medullary thyroid cancer: The FDA granted breakthrough Therapy designation for loXO-292 for the treatment of patients with non-small cell lung cancer and medulloid thyroid cancer (MTC) with the RET gene variant. Loxo-292 achieved an overall response rate of 77% in patients with RET fusion positive tumors. The overall response rate was 77% in patients with non-small cell lung cancer and 45% in patients with RET mutation-positive MTC. (PMID: 31118272, PMID: 29657135, PMID: 29912274, PMID: 29657135)