IDENTIFICATION OF EPIDERMAL GROWTH-FACTOR RECEPTOR AND C-ERBB2 PATHWAY INHIBITORS BY CORRELATION WITH GENE-EXPRESSION PATTERNS

Background: Growth factor receptor-signaling pathways are potentially important targets for anticancer therapy, The interaction of anticance r agents with specific molecular targets can be identified by correlat ing target expression patterns with cytotoxicity patterns, We sought t o identify new agents that target and inhibit the activity of the epid ermal growth factor (EGF) receptor and of c-erbB2 (also called HER2 or neu), by correlating EGF receptor, transforming growth factor (TGF)-a lpha. (a ligand for EGF receptor), and c-erbB2 messenger RNA (mRNA) ex pression levels with the results of cytotoxicity assays of the 49 000 compounds in the National Cancer Institute (NCI) drug screen database, Methods: The levels of mRNAs were measured and used to generate a mol ecular target database for the 60 cell lines of the NCI anticancer dru g screen, The computer analysis program, COMPARE, was used to search f or cytotoxicity patterns in the NCI drug screen database that were hig hly correlated with EGF receptor, TGF-alpha, or c-erbB2 mRNA expressio n 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-inh ibiting compounds were tested for effects on antibody-induced ErbB2 ty rosine kinase activity, Results: EGF receptor mRNA and TGF-alpha mRNA levels were highest in cell lines derived from renal cancers, and c-er bB2 mRNA levels were highest in cells derived from breast, ovarian, an d colon cancers. Twenty-five compounds with high correlation coefficie nts (for cytotoxicity and levels of the measured mRNAs) were tested as inhibitors of the EGF receptor or c-erbB2 signaling pathways; 14 comp ounds were identified as inhibitors of these pathways. The most potent compound, B4, inhibited autophosphorylation (which occurs following a ctivation) of ErbB2 by 50% in whole cells at 7.7 mu M, Conclusions: No vel EGF receptor or c-erbB2 pathway inhibitors can be identified in th e NCI drug screen by correlation of cytotoxicity patterns with EGF rec eptor or c-erbB2 mRNA expression levels.