In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 5455-5455
Abstract:
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-resistant cell lines, using originally AZD6244-senstive cell lines, M14 and COLO-205. The half maximal inhibitory concentration (IC50) values for AZD6244 in two acquired resistant cell lines were 34 fold and 200 fold higher than those of their parent cell lines, respectively. Protein levels of TCF4 in the acquired resistant cell lines were higher than those in the sensitive parent cell lines. Our study results suggest that increase expression of TCF4 may be associated with both intrinsic and acquired resistance to MEK inhibitors. Citation Format: Bon-Kwan Goo, Eun-Hye Hur, Yunsuk Choi, Sung-Doo Kim, Jung Jin Hwang, Choung-Soo Kim, Kyun Seop Bae, Jene Choi, Suk Young Cho, Sang-Hwa Yang, Je-Hwan Lee. Resistance to a MEK inhibitor (AZD6244): Its association with increased expression of transcription factor 4. [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 5455. doi:10.1158/1538-7445.AM2014-5455
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2014-5455
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2014
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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