Abstract 2175: Genomic and transcriptional profiling characterizes the molecular basis for response to cediranib and temsirolimus in endometrial cancer cells

Abstract

Abstract Well-characterized cell lines serve as good models to understand endometrial tumorigenesis, which is highly dependent upon two pathways, PTEN/PI3kinase/AKT/ mTOR and VEGF/VEGFR/PDGFR. These studies describe (1) a genome wide SNP and copy number variation analysis coupled with (2) expression array profiling to fully characterize how the genomic alterations present are reflected in the level of gene expression of critical cancer-associated transcripts in four endometrial cancer cell lines. Further, the cells were profiled for sensitivity and resistance to agents which disrupt the two critical pathways, temsirolimus against mTOR and cederanib against VEGFR/PDGFR. Hec50co cells represent poorly differentiated adenocarcinoma with serous subdifferentiation; RL95-2 and KLE represent moderately differentiated adenocarcinoma, and Ishikawa H cells represent relatively well differentiated hormone response endometrial adenocarcinoma. Affymetrix genome wide microarray SNP6.0 and gene expression microarray U133 analyses were carried out for each cell line. Cells were treated with temsirolimus or cediranib, and relative sensitivity was assigned based upon the IC50 for each agent. RL95-2 cells exhibited the fewest number of copy number variants with 132 chromosomal locations showing changes. Most of the 132 loci involved extra copies of chromosomal fragments, 119 show gains resulting in three or four copies, while 13 chromosomal segments showed only one copy. KLE cells contained the most chromosomal abnormalities with a total of 857 changes. Ishikawa H cells had the second fewest chromosomes copy number changes, and Hec50co cells exhibited the second highest number of anomalies. One of the most interesting findings was the strong association between copy number and relative mRNA expression levels. For many genes, there was a direct relationship between increased copy number and an increased level of gene expression. One good example was Hec50co cells, in which a region of chromosome 4q had undergone duplication resulting in a copy number of four. All three genes within the amplified region demonstrated a high level of mRNA expression when compared to Ishikawa H cells with the normal copy number of two. The same relationship was seen with the reduction or loss of both alleles in that the mRNA levels for these genes were reduced. Relative sensitivity to molecular therapy was also predicted by some of the findings. For example, Hec50co cells amplified the PDGFR gene (four copies), resulting in over-expression of this transcript which was correlated with resistance to cediranib, the VEGFR/PDGFR tyrosine kinase inhibitor. In conclusion, genomic and transcriptional data correlated with drug sensitivity provide a molecular characterization predictive of drug response. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2175.