Abstract 5455: Resistance to a MEK inhibitor (AZD6244): Its association with increased expression of transcription factor 4

The important role of Ras/Raf/MEK/ERK pathway in carcinogenesis has led to clinical development of MEK inhibitors for treatment of various cancers. Although recent studies have demonstrated impressive antitumor activities of the agents, many tumors show intrinsic and acquired resistance to MEK inhibitors. We tried to find biomarkers that were associated with intrinsic or acquired resistance to a MEK inhibitor (AZD6244) by public microarray data acquisition and development of AZD6244-resistance cell lines. First, we analyzed a set of genome-wide gene expression profiling data from 6 sensitive and 6 resistant cell lines of various tissue origins to identify candidate genes whose expression changes are associated with resistant or sensitive responses to AZD6244. Of 62 differentially expressed genes, we selected Transcription Factor 4 (TCF4) gene as a potential drug resistance marker for further analysis because degree of increased expression of TCF4 in resistance cell lines was relatively high and a previous study suggests that TCF4 functions as an oncogene in human colon cancers. The mRNA levels of TCF4 in AZD6244 resistant cell lines were significantly elevated than those in sensitive cell lines. The siRNA was used for the targeted silencing of TCF4 to elucidate the role of increased expression of TCF4 in intrinsic resistance to AZD6244. TCF4 siRNA significantly enhanced susceptibility of a AZD6244-resistant cell line, LOXIMVI, to AZD6244. Next, we established AZD6244-resistan...

Source: Cancer Research - September 30, 2014 Category: Cancer & Oncology Authors: Goo, B.-K., Hur, E.-H., Choi, Y., Kim, S.-D., Hwang, J. J., Kim, C.-S., Bae, K. S., Choi, J., Cho, S. Y., Yang, S.-H., Lee, J.-H. Tags: Experimental and Molecular Therapeutics Source Type: research