|Tumor Type||Primary Site|
Proto-oncogene tyrosine-protein kinase receptor RET, activates the MAPK pathway for cell proliferation and the PI3K/AKT pathway for cell survival. RET activating mutations and rearrangements are common in medullary thyroid carcinomas. 25-30% of medullary thyroid carcinomas are associated with germline RET mutations. In these germline mutations, the most commonly affected codons are 609, 611, 618, 620 (exon 10) and 634 (exon 11), encoding for the extracellular cysteine-rich domain, and codons 768 (exon 13) and 804 (exon 14) of the intracellular tyrosine kinase domain. Sporadic RET mutations have been reported in 61.5% of medullary thyroid carcinomas. In sporadic cases, the M918T mutation is most commonly reported and may indicate a poor prognosis. Given these identified molecular alterations, therapies targeting the RET signaling pathway have been used and shown to provide advantages over traditional cytotoxic therapy with regard to disease response. There are multiple ongoing clinical trials on cabozantinib (tyrosine kinase inhibitor), sorafenib (multikinase inhibitor), and everolimus (mTOR inhibitor).