Dysregulation of EGFR pathway in EphA2 cell subpopulation significantly associates with poor prognosis in colorectal cancer

M. De Robertis, L. Loiacono, C. Fusilli, M.L. Poeta, T. Mazza, M. Sanchez, L. Marchionni, E. Signori, G. Lamorte, A.L. Vescovi, J. Garcia-Foncillas, V.M. Fazio

Research output: Contribution to journalArticlepeer-review


Purpose: 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. Experimental Design: Gene expression analysis was performed in EphA2high cells 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. �2016 AACR.
Original languageEnglish
Pages (from-to)159-170
Number of pages12
JournalClinical Cancer Research
Issue number1
Publication statusPublished - 2017


  • activating transcription factor 2
  • cetuximab
  • ephrin receptor A2
  • epidermal growth factor receptor
  • K ras protein
  • microRNA
  • microRNA 200a
  • microRNA 26b
  • non receptor protein tyrosine phosphatase 12
  • unclassified drug
  • EGFR protein, human
  • EphA2 receptor, human
  • ephrin A2
  • tumor marker
  • aged
  • animal cell
  • animal experiment
  • animal model
  • animal tissue
  • Article
  • Atf2 gene
  • cancer chemotherapy
  • cancer prognosis
  • cancer staging
  • cell subpopulation
  • colorectal cancer
  • controlled study
  • disease association
  • drug effect
  • drug response
  • Efna1 gene
  • Egfr gene
  • EphA2 gene
  • female
  • gene expression profiling
  • gene identification
  • gene mutation
  • human
  • major clinical study
  • male
  • mouse
  • nonhuman
  • oncogene K ras
  • Ptpn12 gene
  • signal transduction
  • tumor gene
  • animal
  • biological model
  • cancer grading
  • cancer stem cell
  • colorectal tumor
  • disease model
  • genetics
  • immunohistochemistry
  • immunophenotyping
  • Kaplan Meier method
  • metabolism
  • mortality
  • pathology
  • prognosis
  • Animals
  • Biomarkers, Tumor
  • Colorectal Neoplasms
  • Disease Models, Animal
  • Ephrin-A2
  • Gene Expression Profiling
  • Humans
  • Immunohistochemistry
  • Immunophenotyping
  • Kaplan-Meier Estimate
  • Male
  • Mice
  • Models, Biological
  • Neoplasm Grading
  • Neoplastic Stem Cells
  • Prognosis
  • Receptor, EphA2
  • Receptor, Epidermal Growth Factor
  • Signal Transduction


Dive into the research topics of 'Dysregulation of EGFR pathway in EphA2 cell subpopulation significantly associates with poor prognosis in colorectal cancer'. Together they form a unique fingerprint.

Cite this