Identification of molecular mechanisms for cellular drug resistance by combining drug activity and gene expression profiles

Abstract

Acquired drug resistance is a major problem in cancer treatment. To explore the genes involved in chemosensitivity and resistance, 10 human tumour cell lines, including parental cells and resistant subtypes selected for resistance against doxorubicin, melphalan, teniposide and vincristine, were profiled for mRNA expression of 7400 genes using cDNA microarray technology. The drug activity of 66 cancer agents was evaluated on the cell lines, and correlations between drug activity and gene expression were calculated and ranked. Hierarchical clustering of drugs based on their drug -gene correlations yielded clusters of drugs with similar mechanism of action. Genes correlated with drug sensitivity and resistance were imported into the PathwayAssist software to identify putative molecular pathways involved. A substantial number of both proapoptotic and antiapoptotic genes such as signal transducer and activator of transcription 1, mitogen-activated protein kinase 1 and focal adhesion kinase were found to be associated to drug resistance, whereas genes linked to cell cycle control and proliferation, such as cell division cycle 25A and signal transducer of activator of transcription 5A, were associated to general drug sensitivity. The results indicate that combined information from drug activity and gene expression in a resistance-based cell line panel may provide new knowledge of the genes involved in anticancer drug resistance and become a useful tool in drug development.

Molecular Pathways: Interferon/Stat1 Pathway: Role in the Tumor Resistance to Genotoxic Stress and Aggressive Growth

“…STAT1 was one of the top genes whose expression positively correlated with resistance to doxorubicin and topoisomerase-II inhibitors (27). Upregulation of STAT1 in doxorubicin-resistant cell lines was accompanied by the upregulation of ISGs that overlapped, in part, with the IRDS genes (28).…”

A multiple marker analysis of apoptosis-associated protein expression in non-small cell lung cancer in a Chinese population

“…Studies have shown that cancer cells invariably have abnormalities in one or more apoptotic pathways, determining a survival advantage of these cells over their normal counterparts [1,2,[6][7][8][9]. Furthermore, abnormalities in the apoptotic response also play a role in the development of drug resistance by cancer cells [1,4,6,[10][11][12][13][14]. There is growing interest in the development of therapeutic strategies that kill can-232 232 232 232 232 [16] by at least two pathologists.…”

In Vitro Drug Sensitivity-Gene Expression Correlations Involve a Tissue of Origin Dependency

“…9 For ease of presentation we selected only genes whose expression pattern had a standard deviation greater than one, leaving 324 out of 3903 genes (including all 3903 genes did not change the qualitative results). We choose to study the difference between clustering CCPs and original measurements for average linkage and the Euclidean distance metric.…”

“…The biological data used in the present paper is described in full in Rickardson et al 9 Briefly, a cell-line panel (Table 1) consisting of the parental cell lines RPMI 8226 (myeloma), CCRF-CEM (leukemia), U937 GTB (lymphoma), and NCI-H69 (small cell lung cancer); the drug-resistant sublines 8226/Dox40 8226/LR5, CEM/VM-1, U937 vcr, and H69AR; and the primary resistant ACHN (renal adenocarcinoma) was assayed. For each cell line 3903 gene activities were measured successfully using our in-house cDNA microrrray gene expression system.…”