A novel cell‐based Screening System Identifies Adefovir‐dipivoxil as Suppressor of RET expression in medullary thyroid carcinoma

Abstract

The aberrant gene expression is often associated with the progression of several cancers and hence targeting the transcriptional activation of oncogenes using small‐molecules could be a potential strategy for controlling the tumor growth and development. The gain‐of‐function mutation in the RET proto‐oncogene has been identified as the major cause for the development of medullary thyroid carcinoma (MTC), which is a part of multiple endocrine neoplasia type 2 (MEN2) syndrome. In this study we utilized a cell‐based bioluminescence reporter system in which the luciferase gene expression is driven by the RET promoter to screen for drug‐like molecules that potentially suppress the transcription of this gene. Using this system, we identified adefovir‐ dipivoxil as a transcriptional inhibitor for the RET gene, which further suppressed the endogenous RET protein expression in MTC TT cells. Consistent with this effect, adefovir‐dipivoxil also inhibited RET dependent TT cell proliferation and increased apoptosis in these cells. These results highlight the potential of the cell‐based screening assay to identify transcriptional inhibitors for other oncogenes.