Abstract
Growing evidence supports the concept of oncogene dependence for cancer development; inhibition of the initiating oncogene can result in revertion of the neoplastic phenotype. The outstanding role of the RET proto-oncogene in the development of medullary thyroid carcinoma (MTC) is well established. With the emerging knowledge concerning the signal transduction pathways leading to subsequent neoplastic transformation, oncogenic activated RET becomes a highly attractive target for selective cancer therapy. A variety of novel approaches that target RET directly or indirectly have recently emerged and an increasing number are currently being assessed in clinical trials. In view of these findings, it becomes strikingly obvious that inhibition of RET oncogene function can be a viable option for the treatment of MTC. We summarize the current evidence for RET involvement in the etiology of MTC, and the therapeutic targeting of this process in preclinical and clinical studies.
Key Points
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Mutations in the RET proto-oncogene are responsible for the development of medullary thyroid carcinoma, which occurs sporadically or as part of the inherited cancer syndrome, multiple endocrine neoplasia type 2
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RET is a tyrosine kinase receptor implicated in developmental processes and neural survival
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Mutations activate RET in a constitutive fashion which, in turn, results in aberrant stimulation of downstream signal transduction pathways that mediate cell proliferation and survival
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Several strategies have been developed to block hyperactive RET in preclinical models of medullary thyroid carcinoma, and these models show that RET inhibition results in a loss of neoplastic phenotypes
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Some approaches to target RET have already entered investigation in clinical trials
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Drosten, M., Pützer, B. Mechanisms of Disease: cancer targeting and the impact of oncogenic RET for medullary thyroid carcinoma therapy. Nat Rev Clin Oncol 3, 564–574 (2006). https://doi.org/10.1038/ncponc0610
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DOI: https://doi.org/10.1038/ncponc0610
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