Abstract
Introduction: The RET gene encodes a receptor tyrosine kinase essential for ontogenesis of the enteric nervous system and kidney. Following identification of RET, it was found that somatic rearrangements of this gene, conventionally designated as RET/PTC, are frequently present in papillary thyroid carcinoma. Subsequently, activating germ line point mutations of RET were identified as being responsible for the hereditary medullary thyroid carcinoma syndromes MEN2A, MEN2B and FMTC. RET rearrangements have recently been identified in a small fraction of lung adenocarcinomas.
Area covered: The authors review the current field concerning the RET gene and protein, its involvement in cancer and the preclinical and clinical studies which highlight its role as a potentially important therapeutic target for several cancers.
Expert opinion: Many multitargeted inhibitors which crossreact with RET have been developed and investigated in clinical trials targeting many cancer indications. In particular, VEGFR/PDGFR inhibitors, widely explored as antiangiogenics, have been intensively studied in thyroid carcinoma patients. Notwithstanding the efficacy observed with such agents, their common clinical activity in thyroid carcinoma is of short duration and includes frequent and severe side effects, limiting their therapeutic action. These findings are discussed and the need for improved, more specific RET-targeting drugs is highlighted.
Acknowledgements
We wish to thank Dr Arturo Galvani for helpful discussion and critical reading of the manuscript, and Dr Silvana Pilotti, Dr Paola Romeo and Dr Emanuela Minna for contributing to Figures, and Silvia Grassi for secretarial assistance. This work was supported by grants from Associazione Italiana per la Ricerca sul Cancro (AIRC) and from Fondazione Berlucchi Project ‘Identification of novel prognostic markers and therapeutic strategies for medullary thyroid carcinoma’.
Notes
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