The tyrosine kinase inhibitor ZD6474 blocks proliferation of RET mutant medullary thyroid carcinoma cells.

Oncogenic conversion of the RET tyrosine kinase is a frequent feature of medullary thyroid carcinoma (MTC). ZD6474 (vandetanib) is a ATP-competitive inhibitor of RET, EGFR and VEGFRs kinases. Here, we have studied ZD6474 mechanism of action in TT and MZ-CRC-1 human MTC cell lines, carrying the cysteine 634 to tryptophan (C634W) and the methionine 918 to threonine (M918T) RET mutation, respectively. ZD6474 blunted MTC cell proliferation and RET, Shc and p44/p42 MAPK phosphorylation. Single receptor knock-down by RNA interference showed that MTC cells depended on RET for proliferation. Adoptive expression of the ZD6474-resistant V804M RET mutant rescued proliferation of TT cells under ZD6474 treatment, showing that RET is a key ZD6474 target in these MTC cells. Upon RET inhibition, adoptive stimulation of EGFR partially rescued TT cell proliferation, MAPK signaling, and expression of cell cycle-related genes. This suggests that simultaneous inhibition of RET and EGFR by ZD6474 may overcome the risk of MTC cells escape from RET blockade through compensatory over-activation of EGFR.