Medullary thyroid carcinoma (MTC) is a rare tumor arising from neural crest-derived parafollicular C cells. MTC occurs either in sporadic or familial form. A key role in the development of MTC is played by the RET proto-oncogene, as virtually all familial and half sporadic MTC cases feature RET point mutations. These mutations lead to the constitutive activation of the RET kinase and its oncogene conversion. Mutations targeting extracellular cysteines cause disulfide-bond mediated RET dimerization. Crystal structure of the RET kinase domain has shown that the most commonly found mutation, M918T, instead alters the structure of the RET catalytic domain. Once activated, RET triggers well characterized intracellular signaling cascades including those involving RAS-ERK and PI3K-AKT pathways. Accordingly, on one hand, RAS mutations have been recently described by others in a significant fraction of RET negative MTC; on the other hand, phosphorylation of AKT and of phospho-ribosomal protein S6 (pS6), a downstream target of mTOR, was evident in the vast majority of MTC samples, independent from RET mutational status and particularly in the node mets compared with the matched primary MTC, suggesting a role in metastatic dissemination. This knowledge points to RET or AKT/mTOR targeting as promising therapeutic strategies for MTC.
Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding: No specific grant from any funding agency in the public, commercial or not-for-profit sector.