title: Differential transcriptional effects of EGFR inhibitors.
abstract: EGF and its receptor EGFR serve as a paradigm for signaling in cell, molecular and tumor biology. EGFR inhibitors, drugs targeting the intracellular kinase activity and antibodies targeting the extracellular ligand binding, are used to treat breast, lung, colon and other cancers. Nominally affecting the same target, inhibitors have different effects, suggesting that use of inhibitor combinations may provide beneficial in cancer treatment. To explore the specific and the common transcriptional effects of EGFR inhibitors, we present metaanalysis of 20 individual studies comprising 346 microarrays. We identified specific gene subsets regulated by kinase inhibitors, those regulated using antibodies and by suppressing EGFR expression using miR-7. Unreported before, the inhibitors prominently induce lysosome components. All inhibitors rely on related sets of transcription factors and protein kinases, both for transcriptional induction and suppression. However, we find that Gefitinib suppresses apoptosis inhibitors, while inducing cell-cycle inhibitors; conversely, Erlotinib suppresses cell-cycle and cell migration genes, while inducing proapoptotic genes. EGFR-targeting antibodies specifically suppress cell motility, developmental and differentiation processes, while inducing the contractile apparatus. miR-7, distinctively, suppresses cell-cycle genes, while inducing transcription machinery. These metaanalysis results suggest that different inhibitors have overlapping but quite distinct effects in target cells. Judicial use of EGFR-targeting combinations, i.e., simultaneous use of antibodies and multiple kinase inhibitors, may provide more effective cancer treatments with fewer side-effects and avoid development of resistance. We expect, moreover, that specific drug combination treatments can be fine-tuned to achieve specific, personalized results.
authors.affiliation: The R.O. Perelman Department of Dermatology, Department of Biochemistry and Molecular Pharmacology and the NYU Cancer Institute, NYU Langone Medical Center, New York, New York, United States of America.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Blumenberg
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D004338:Drug Combinations; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D046228:Microarray Analysis; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D057285:Precision Medicine; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D000970:Antineoplastic Agents; D004338:Drug Combinations; D066246:ErbB Receptors; D035683:MicroRNAs; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; C549242:MIRN7-1 microRNA, human; C512478:EGFR protein, human