title: Dysregulation of EGFR Pathway in EphA2 Cell Subpopulation Significantly Associates with Poor Prognosis in Colorectal Cancer.
abstract: OBJECTIVE
  EphA2 receptor is involved in multiple cross-talks with other cellular networks, including EGFR, FAK, and VEGF pathways, with which it collaborates to stimulate cell migration, invasion, and metastasis. Colorectal cancer (CRC) EphA2 overexpression has also been correlated to stem-like properties of cells and tumor malignancy. We investigated the molecular cross-talk and miRNAs modulation of the EphA2 and EGFR pathways. We also explored the role of EphA2/EGFR pathway mediators as prognostic factors or predictors of cetuximab benefit in patients with CRC.
  
  
  METHODS
  Gene expression analysis was performed in EphA2highcells isolated from CRC of the AOM/DSS murine model by FACS-assisted procedures. Six independent cohorts of patients were stratified by EphA2 expression to determine the potential prognostic role of a EphA2/EGFR signature and its effect on cetuximab treatment response.
  
  
  RESULTS
  We identified a gene expression pattern (EphA2, Efna1, Egfr, Ptpn12, and Atf2) reflecting the activation of EphA2 and EGFR pathways and a coherent dysregulation of mir-26b and mir-200a. Such a pattern showed prognostic significance in patients with stage I-III CRC, in both univariate and multivariate analysis. In patients with stage IV and WT KRAS, EphA2/Efna1/Egfr gene expression status was significantly associated with poor response to cetuximab treatment. Furthermore, EphA2 and EGFR overexpression showed a combined effect relative to cetuximab resistance, independently from KRAS mutation status.
  
  
  CONCLUSIONS
  These results suggest that EphA2/Efna1/Egfr genes, linked to a possible control by miR-200a and miR-26b, could be proposed as novel CRC prognostic biomarkers. Moreover, EphA2 could be linked to a mechanism of resistance to cetuximab alternative to KRAS mutations. Clin Cancer Res; 23(1); 159-70. ©2016 AACR.
authors.affiliation: Laboratory of Genetic and Clinical Pathology, University Campus Bio-Medico of Rome, Rome, Italy. fazio@unicampus.it mariangela.derobertis@gmail.com.
authors.forename: Mariangela
authors.initials: M
authors.lastname: De Robertis
authors.affiliation: Laboratory of Genetic and Clinical Pathology, University Campus Bio-Medico of Rome, Rome, Italy.|Laboratory of Oncology, IRCCS "Casa Sollievo della Sofferenza," San Giovanni Rotondo (Fg), Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Loiacono
authors.affiliation: Unit of Bioinformatics, IRCCS "Casa Sollievo della Sofferenza," San Giovanni Rotondo (Fg), Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Fusilli
authors.affiliation: Department of Bioscience, Biotechnology and Biopharmaceutics, University of Bari, Bari, Italy.
authors.forename: Maria Luana
authors.initials: ML
authors.lastname: Poeta
authors.affiliation: Unit of Bioinformatics, IRCCS "Casa Sollievo della Sofferenza," San Giovanni Rotondo (Fg), Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Mazza
authors.affiliation: Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Sanchez
authors.affiliation: Center for Computational Genomics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Luigi
authors.initials: L
authors.lastname: Marchionni
authors.affiliation: Laboratory of Molecular Pathology and Experimental Oncology, Institute of Translational Pharmacology, National Research Council (CNR), Rome, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Signori
authors.affiliation: IRCCS "Casa Sollievo della Sofferenza," San Giovanni Rotondo (Fg), Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lamorte
authors.affiliation: IRCCS "Casa Sollievo della Sofferenza," San Giovanni Rotondo (Fg), Italy.
authors.forename: Angelo Luigi
authors.initials: AL
authors.lastname: Vescovi
authors.affiliation: Translational Oncology Division, Oncohealth Institute, FIIS-Fundacion Jimenez Diaz, Madrid, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Garcia-Foncillas
authors.affiliation: Laboratory of Genetic and Clinical Pathology, University Campus Bio-Medico of Rome, Rome, Italy. fazio@unicampus.it mariangela.derobertis@gmail.com.|Laboratory of Oncology, IRCCS "Casa Sollievo della Sofferenza," San Giovanni Rotondo (Fg), Italy.
authors.forename: Vito Michele
authors.initials: VM
authors.lastname: Fazio
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D004195:Disease Models, Animal; D036383:Ephrin-A2 / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D016130:Immunophenotyping; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008954:Models, Biological; D060787:Neoplasm Grading; D014411:Neoplastic Stem Cells / Q000378:metabolism; D011379:Prognosis; D036104:Receptor, EphA2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D014408:Biomarkers, Tumor; C000623258:EPHA2 protein, human; D036383:Ephrin-A2; C512478:EGFR protein, human; D066246:ErbB Receptors; D036104:Receptor, EphA2