Key signaling pathways in thyroid cancer

Whole genome sequencing approaches have provided unprecedented insights into the genetic lesions responsible for the onset, progression and dedifferentiation of various types of thyroid carcinomas. Through these efforts, the MAPK and PI3K signaling cascades have emerged as the main activation pathways implicated in thyroid tumorigenesis. The nature of these essential pathways is highly complex, with hundreds of components, multiple points of crosstalk, different subcellular localizations and with the ability to potentially regulate many cellular processes. Small-molecule inhibitors targeting key kinases of these pathways hold great promise as novel therapeutics and several have reached clinical trials. However, while some remarkable responses have been reported, the development of resistance remains a matter of concern and limits the benefit for patients. In this review, we discuss the latest findings on the major components of the MAPK and PI3K pathways, including their mechanisms of activation in physiological and pathological contexts, their genetic alterations with respect to the different types of thyroid carcinomas and the more relevant drugs designed to block their activity.Supported by the following grants: GCB14142311CRES from the Spanish Foundation against Cancer (F-AECC), SAF2013-44709-R and SAF2016-75531-R from the Ministry of Economy and Competitiveness, RD12/0036/0030 and Ciberonc from the Carlos III Health Institute, (Spain), and the European Regional Development Fund (FEDER).Peer reviewe