title: Transcriptional changes associated with resistance to inhibitors of epidermal growth factor receptor revealed using metaanalysis.
abstract: BACKGROUND
  EGFR is important in maintaining metabolic homeostasis in healthy cells, but in tumors it activates downstream signaling pathways, causing proliferation, angiogenesis, invasion and metastasis. Consequently, EGFR is targeted in cancers using reversible, irreversible or antibody inhibitors. Unfortunately, tumors develop inhibitor resistance by mutations or overexpressing EGFR, or its ligand, or activating secondary, EGFR-independent pathways.
  
  
  METHODS
  Here we present a global metaanalysis comparing transcriptional profiles from matched pairs of EGFR inhibitor-sensitive vs. -resistant cell lines, using 15 datasets comprising 274 microarrays. We also analyzed separately pairs of cell lines derived using reversible, irreversible or antibody inhibitors.
  
  
  RESULTS
  The metaanalysis identifies commonalities in cell lines resistant to EGFR inhibitors: in sensitive cell lines, the ontological categories involving the ErbB receptors pathways, cell adhesion and lipid metabolism are overexpressed; however, resistance to EGFR inhibitors is associated with overexpression of genes for ErbB receptors-independent oncogenic pathways, regulation of cell motility, energy metabolism, immunity especially inflammatory cytokines biosynthesis, cell cycle and responses to exogenous and endogenous stimuli. Specifically in Gefitinib-resistant cell lines, the immunity-associated genes are overexpressed, whereas in Erlotinib-resistant ones so are the mitochondrial genes and processes. Unexpectedly, lines selected using EGFR-targeting antibodies overexpress different gene ontologies from ones selected using kinase inhibitors. Specifically, they have reduced expression of genes for proliferation, chemotaxis, immunity and angiogenesis.
  
  
  CONCLUSIONS
  This metaanalysis suggests that 'combination therapies' can improve cancer treatment outcomes. Potentially, use of mitochondrial blockers with Erlotinib, immunity blockers with Gefitinib, tyrosine kinase inhibitors with antibody inhibitors, may have better chance of avoiding development of resistance.
authors.affiliation: The R.O.Perelman Department of Dermatology, New York, USA. Sidra.Younis@nyumc.org.|Department of Biochemistry and Molecular Pharmacology, New York, USA. Sidra.Younis@nyumc.org.|NYU Cancer Institute, NYU Langone Medical Center, New York, USA. Sidra.Younis@nyumc.org.|Department of Biochemistry, Quaid-i-Azam University, Islamabad, 45320, Pakistan. Sidra.Younis@nyumc.org.
authors.forename: Sidra
authors.initials: S
authors.lastname: Younis
authors.affiliation: Department of Biochemistry, Quaid-i-Azam University, Islamabad, 45320, Pakistan. qjaved6@gmail.com.
authors.forename: Qamar
authors.initials: Q
authors.lastname: Javed
authors.affiliation: The R.O.Perelman Department of Dermatology, New York, USA. Miroslav.Blumenberg@nyumc.org.|Department of Biochemistry and Molecular Pharmacology, New York, USA. Miroslav.Blumenberg@nyumc.org.|NYU Cancer Institute, NYU Langone Medical Center, New York, USA. Miroslav.Blumenberg@nyumc.org.|NYU School of Medicine, 455 First Avenue, New York, 10016, USA. Miroslav.Blumenberg@nyumc.org.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Blumenberg
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D030541:Databases, Genetic; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors