Mechanisms of RET signaling in cancer: Current and future implications for targeted therapy

De-regulation of RET signaling by oncogenic mutation, gene rearrangement, overexpression or transcriptional up-regulation is implicated in several human cancers of neuroendocrine and epithelial origin (thyroid, breast, lung). Understanding how RET signaling mechanisms associated with these oncogenic events are deregulated, and their impact in the biological processes driving tumor formation and progression, as well as response to treatment, will be crucial to find and develop better targeted therapeutic strategies. In this review we emphasie the distinct mechanisms of RET signaling in cancer and summarise current knowledge on small molecule inhibitors targeting the tyrosine kinase domain of RET as therapeutic drugs in RET-positive cancers.