Oncotarget. 2017 Jun 20;8(25):41387-41400. doi: 10.18632/oncotarget.17866.

Induction of immunoglobulin transcription factor 2 and resistance to MEK inhibitor in melanomacells.

Hur EH, Goo BK, Moon J, Choi Y, Hwang JJ, Kim CS, Bae KS, Choi J, Cho SY, Yang SH, Seo J, Lee G, Lee JH.

Abstract

Primary or acquired resistance to MEK inhibitors has been a barrier to successful treatment with MEK inhibitors in many tumors. In this study, we analyzed genome-wide gene expression profiling data from 6 sensitive and 6 resistant cell lines to identify candidate genes whose expression changes are associated with responses to a MEK inhibitor, selumetinib (AZD6244). Of 62 identified differentially expressed genes, we selected Immunoglobulin Transcription Factor 2, also known as transcription factor 4 as a potential drug resistance marker for further analysis. This was because the ITF-2 expression increase in resistant cell lines was relatively high and a previous study has suggested that ITF-2 functions as an oncogene in human colon cancers. We also established an AZD6244 resistant cell line (M14/AZD-3) from an AZD6244 sensitive M14 cell line. The expression of the ITF-2 was elevated both in primary AZD6244 resistant cell line, LOX-IMVI and acquired resistant cell line, M14/AZD-3. Targeted silencing of ITF-2 by siRNA significantly enhanced susceptibility to AZD6244 in resistant cells. Wnt/β-catenin pathway was activated through direct interaction of p-ERK and GSK3β. Our results suggest that up-regulation of the ITF-2 gene expression is associated with cellular resistance to MEK inhibitors, and activation of Wnt signaling pathway through interaction of p-ERK and GSK3β seems to be a mechanism for increase of ITF-2.

KEYWORDS:

ITF-2; MAPK; beta-catenin; melanoma; resistance

PMID:

28574827

PMCID:

PMC5522248

DOI:

10.18632/oncotarget.17866