Abstract 3208: Identification and characterization of a small molecule involved in the downregulation of RET transcription in MTC

Abstract

Abstract The gain of function mutations in the RET proto-oncogene, which results in the constitutive activation of the mitogenic pathways, were found mainly in Medullary Thyroid Carcinoma (MTC). In our study, a new therapeutic strategy has been explored to repress the expression of the RET gene by targeting the transcriptional activation of this gene with small molecules. The transcriptional inhibitor of the RET gene was initially screened from the NCI chemical libraries using the cell-based luciferase reporter gene assay, which has a promoter sequence identical to the RET promoter. As a result of our screening effort, a small molecule, nonactin, has been identified as a potential lead compound, downregulating the transcriptional activity of the RET gene promoter. The effect of this molecule in the downregulation of the RET mRNA levels and the protein levels was confirmed by RT-PCR and western blotting respectively. We also observed that Egr1 expression is downergulated in a dose dependent manner by this small molecule, which is in correlation with the RET downregulation. The RET promoter has a highly conserved GC rich region, which acts as a binding site for Egr-1, which is involved in the transcription of many growth factor genes. Thus, we conclude that Egr1 would be one of important transcriptional factors involved in the activation of the RET and nonactin inhibits the expression of Egr1, which in turn downregulates the transcription of RET oncogene. Citation Format: Vishnu Muthuraj Kumarasamy, Yoon-Joo Shin, Daekyu Sun. Identification and characterization of a small molecule involved in the downregulation of RET transcription in MTC. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3208. doi:10.1158/1538-7445.AM2014-3208