The RET kinase has emerged as a promising target for the therapy of medullary 
thyroid cancers (MTC) and of a subset of papillary thyroid cancers. NVP-AST487, 
a N,N'-diphenyl urea with an IC(50) of 0.88 mumol/L on RET kinase, inhibited RET 
autophosphorylation and activation of downstream effectors, and potently 
inhibited the growth of human thyroid cancer cell lines with activating 
mutations of RET but not of lines without RET mutations. NVP-AST487 induced a 
dose-dependent growth inhibition of xenografts of NIH3T3 cells expressing 
oncogenic RET, and of the MTC cell line TT in nude mice. MTCs secrete 
calcitonin, a useful indicator of tumor burden. Human plasma calcitonin levels 
derived from the TT cell xenografts were inhibited shortly after treatment, when 
tumor volume was still unchanged, indicating that the effects of RET kinase 
inhibition on calcitonin secretion were temporally dissociated from its 
tumor-inhibitory properties. Accordingly, NVP-AST487 inhibited calcitonin gene 
expression in vitro in TT cells, in part, through decreased gene transcription. 
These data point to a previously unknown physiologic role of RET signaling on 
calcitonin gene expression. Indeed, the RET ligands persephin and GDNF robustly 
stimulated calcitonin mRNA, which was blocked by pretreatment with NVP-AST487. 
Antagonists of RET kinase activity in patients with MTC may result in effects on 
plasma calcitonin that are either disproportionate or dissociated from the 
effects on tumor burden, because RET kinase mediates a physiologic pathway 
controlling calcitonin secretion. The role of traditional tumor biomarkers may 
need to be reassessed as targeted therapies designed against oncoproteins with 
key roles in pathogenesis are implemented.