title: An informatics approach identifying markers of chemosensitivity in human cancer cell lines.
abstract: We have used a sensitive and reproducible method of measuring mRNA expression to compare basal levels of 10 transcripts in the 60 cell lines of the National Cancer Institute's in vitro anticancer drug screen (NCI-ACDS) under conditions of exponential growth. The strongest correlation among these target genes was between levels of CIP1/WAF1 and BAX. Levels of the three major growth arrest and DNA damage-inducible gene transcripts, (GADD34, GADD45, and GADD153), which are coordinately regulated in response to many stresses, were also correlated across the 60 cell lines. Although the stress induction of several of the transcripts studied here has been shown to be dependent on wild-type p53 status, basal levels of only CIP1/WAF1 and BAX were found to correlate with p53 status. As expected, basal expression of O6 alkyl guanine alkyl-transferase correlated well with resistance to O6-alkylating agents (r = -0.44) but not with resistance to alkylators with different mechanisms of action (r = -0.04). When basal expression levels of the 10 genes across the NCI-ACDS panel were compared with sensitivities to a panel of 122 standard chemotherapy agents, the most striking relationship was a strong negative correlation (r = -0.3) between basal BCL-X levels and sensitivity to drugs in all of the mechanistic classes except one class of antimetabolites. Sensitivities to a maximally diverse sample of 1200 from 70,000 compounds tested in the NCI-ACDS of agents were also negatively correlated with BCL-X levels. A novel application of factor analysis revealed that the newly discovered associations were independent of previously demonstrated sensitivity factors such as p53 mutation status and native population doubling time. A similar pattern of correlation was seen for Bcl-X(L) protein levels. Conversely, BAX and BCL2, two other genes associated with regulation of apoptosis, showed no overall correlation with drug sensitivities. This suggests that BCL-X may play a unique role in general resistance to cytotoxic agents, with the cell lines demonstrating relative resistance to 70,000 cytotoxic agents in the NCI-ACDS being characterized by high BCL-X expression.
authors.affiliation: NIH, National Cancer Institute, Biological Research Laboratory, Bethesda, Maryland 20892, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Amundson
authors.forename: T G
authors.initials: TG
authors.lastname: Myers
authors.forename: D
authors.initials: D
authors.lastname: Scudiero
authors.forename: S
authors.initials: S
authors.lastname: Kitada
authors.forename: J C
authors.initials: JC
authors.lastname: Reed
authors.forename: A J
authors.initials: AJ
authors.lastname: Fornace
mesh_terms: D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics*; D001798:Blood Proteins / Q000096:biosynthesis / Q000235:genetics; D016000:Cluster Analysis; D004354:Drug Screening Assays, Antitumor; D015870:Gene Expression; D006801:Humans; D008490:Medical Informatics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis* / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
chemical_list: C494826:BAX protein, human; C494811:BCL2L1 protein, human; D014408:Biomarkers, Tumor; D001798:Blood Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C051541:cell-binding immunoglobulin-like protein, human