RET Mutation in Malignancy

RET encodes a receptor tyrosine kinase involved neural crest development. Oncogenic RET mutations occur frequently in medullary thyroid carcinoma (MTC). Approximately 50-60% of sporadic MTC harbor somatic RET mutations. The presence of these mutations is associated with an inferior prognosis and more aggressive disease. Germline RET mutations are associated with multiple endocrine neoplasia (MEN) 2 or familial medullary thyroid carcinoma. Multi-kinase inhibitors (MKI) including vandetanib and cabozantinib are FDA-approved for the treatment of metastatic or unresectable MTC (regardless of RET mutation status). Reported response rates to these agents range from 20%-45%. These drugs are often associated with toxicities – some (e.g. impaired wound healing, fistula formation, hemorrhage) related to inhibition of other tyrosine kinases, particularly vascular endothelial growth factor receptor 2 (VEGFR-2). Several selective tyrosine kinase inhibitors (TKI) with much greater RET inhibitory potency have been developed including LOXO-292, BLU-667 and RXDX-105. These drugs have shown promising efficacy with significantly lower toxicity in RET-mutated MTC.