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Identification of epidermal growth factor receptor and c-erbB2 pathway inhibitors by correlation with gene expression
K Wosikowski1, D Schuurhuis, K Johnson
1Division of Clinical Sciences, National Cancer Institute, Bethesda, MD 20892, USA.
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.
Insights
Researchers identified novel anticancer agents by correlating drug cytotoxicity with gene expression. This method successfully found 14 compounds inhibiting epidermal growth factor (EGF) receptor and c-erbB2 pathways, offering new therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Growth factor receptor signaling pathways are crucial targets for anticancer therapies.
- Correlating molecular target expression with cytotoxicity patterns aids in identifying effective anticancer agents.
- The epidermal growth factor (EGF) receptor and c-erbB2 (HER2) are significant targets in cancer treatment.
Purpose of the Study:
- To discover novel anticancer agents targeting the EGF receptor and c-erbB2 pathways.
- To correlate messenger RNA (mRNA) expression levels of EGF receptor, TGF-alpha, and c-erbB2 with cytotoxicity data from the NCI drug screen.
- To identify compounds that inhibit the signaling activities of EGF receptor and c-erbB2.
Main Methods:
- Measured mRNA expression levels for EGF receptor, TGF-alpha, and c-erbB2 across 60 NCI anticancer drug screen cell lines.
- Utilized the COMPARE program to identify correlations between mRNA expression patterns and cytotoxicity profiles.
- Validated putative inhibitors by testing their effects on tyrosine phosphorylation, kinase activity, and cell growth.
Main Results:
- Highest EGF receptor and TGF-alpha mRNA levels were observed in renal cancer cell lines.
- Highest c-erbB2 mRNA levels were found in breast, ovarian, and colon cancer cell lines.
- Out of 25 tested compounds, 14 were confirmed as inhibitors of EGF receptor or c-erbB2 signaling, with compound B4 showing potent inhibition of ErbB2 autophosphorylation.
Conclusions:
- Correlation of cytotoxicity patterns with specific mRNA expression levels is an effective strategy for identifying novel inhibitors of EGF receptor and c-erbB2.
- The NCI drug screen database, combined with expression profiling, can yield new anticancer drug candidates targeting key growth factor pathways.