© 1997 by Oxford University Press
Journal Of The National Cancer Institute, Vol 89, 1505-1515, Copyright © 1997 by Oxford University Press
K Wosikowski, D Schuurhuis, K Johnson, KD Paull, TG Myers, JN Weinstein and SE Bates
BACKGROUND: Growth factor receptor-signaling pathways are potentially
important targets for anticancer therapy. The interaction of anticancer
agents with specific molecular targets can be identified by correlating
target expression patterns with cytotoxicity patterns. We sought to
identify new agents that target and inhibit the activity of the epidermal
growth factor (EGF) receptor and of c-erbB2 (also called HER2 or neu), by
correlating EGF receptor, transforming growth factor (TGF)- alpha (a ligand
for EGF receptor), and c-erbB2 messenger RNA (mRNA) expression levels with
the results of cytotoxicity assays of the 49000 compounds in the National
Cancer Institute (NCI) drug screen database. METHODS: The levels of mRNAs
were measured and used to generate a molecular target database for the 60
cell lines of the NCI anticancer drug screen. The computer analysis
program, COMPARE, was used to search for cytotoxicity patterns in the NCI
drug screen database that were highly correlated with EGF receptor,
TGF-alpha, or c-erbB2 mRNA expression patterns. The putative EGF
receptor-inhibiting compounds were tested for effects on basal tyrosine
phosphorylation, in vitro EGF receptor tyrosine kinase activity, and
EGF-dependent growth. Putative ErbB2-inhibiting compounds were tested for
effects on antibody-induced ErbB2 tyrosine kinase activity. RESULTS: EGF
receptor mRNA and TGF- alpha mRNA levels were highest in cell lines derived
from renal cancers, and c-erbB2 mRNA levels were highest in cells derived
from breast, ovarian, and colon cancers. Twenty-five compounds with high
correlation coefficients (for cytotoxicity and levels of the measured
mRNAs) were tested as inhibitors of the EGF receptor or c-erbB2 signaling
pathways; 14 compounds were identified as inhibitors of these pathways. The
most potent compound, B4, inhibited autophosphorylation (which occurs
following activation) of ErbB2 by 50% in whole cells at 7.7 microM.
CONCLUSIONS: Novel EGF receptor or c-erbB2 pathway inhibitors can be
identified in the NCI drug screen by correlation of cytotoxicity patterns
with EGF receptor or c-erbB2 mRNA expression levels.
ARTICLES
Identification of epidermal growth factor receptor and c-erbB2 pathway inhibitors by correlation with gene expression patterns
Division of Clinical Sciences, National Cancer Institute, Bethesda, MD 20892, USA.
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