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Cited by 78Colorectal Cancer Treatments and StudiesHER2/EGFR in Cancer ResearchAxon Guidance and Neuronal Signaling

Dysregulation of EGFR Pathway in EphA2 Cell Subpopulation Significantly Associates with Poor Prognosis in Colorectal Cancer

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De Robertis, Mariangela, Loiacono, Luisa, Fusilli, Caterina, Poeta, Maria Luana, Mazza, Tommaso, Sanchez, Massimo, Marchionni, Luigi, Signori, Emanuela +4 more·2017·Clinical Cancer Research
DOI 10.1158/1078-0432.ccr-16-0709PMC PMC5822042

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Abstract

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. Clin Cancer Res; 23(1); 159–70. ©2016 AACR.

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  • EphR activation has been reported as a mechanism of resistance to cetuximab in CRC and head and neck squamous cell carcinoma, suggesting cross talk between EphR and EGFR can amplify EGFR signaling.

    “Interestingly EphR activation has been reported as mechanism of resistance to cetuximab in CRC and head and neck squamous cell carcinoma and CRC, suggesting that the cross talk between these two classes of RTKs can potentially amplify EGFR signaling(20).”

    From EGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer. (2020) · cites this paper as [20]

    The Introduction (page unavailable) reports that studies in head and neck squamous cell carcinoma and CRC suggested a role for EphA2 in responsiveness to cetuximab. The Results and Discussion (page unavailable) associate high EphA2 expression with poorer cetuximab response in CRC and suggest it may bypass EGFR-pathway inhibition. They do not establish EphR activation as the mechanism or show that crosstalk amplifies EGFR signaling. (LLM, conf=0.83)

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Cited by

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Authors
De Robertis, M., Loiacono, L., Fusilli, C., Poeta, M. L., Mazza, T., Sanchez, M., Marchionni, L., Signori, E., Lamorte, G., Vescovi, A. L., Garcia-Foncillas, J., & Fazio, V. M.
Affiliations
  • 1Laboratory of Genetic and Clinical Pathology, University Campus Bio-Medico of Rome, Rome, Italy.
  • Università Campus Bio-Medico (IT)
  • Casa Sollievo della Sofferenza (IT)
  • University of Bari Aldo Moro (IT)
  • Istituto Superiore di Sanità (IT)
  • Johns Hopkins University (US)
  • Istituto di Farmacologia Traslazionale (IT)
  • 9Translational Oncology Division, Oncohealth Institute, FIIS-Fundacion Jimenez Diaz, Madrid, Spain.
Corresponding author
Fazio, Vito Michele
ORCID
Venue
Clinical Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2017-01-01
Volume
23
Issue
1
Pages
159-170
ISSN
  • 1078-0432 (ISSN-L)
  • 1557-3265
DOI
10.1158/1078-0432.ccr-16-0709
PMC
PMC5822042
OpenAlex
W2465842259
Cited by
78
References
2
Citations by year
2025: 1 · 2024: 12 · 2023: 9 · 2022: 11 · 2021: 14 · 2020: 10 · 2019: 5 · 2018: 8 · 2017: 6 · 2016: 1
FWCI
3.60
Type
journal article
Language
en
Open access
Locations
  • Clinical Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • BOA (University of Milano-Bicocca) (submittedVersion, other-oa)
  • CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion, cc-by)
Funders
  • Regione Lazio–Progetti Imprenditoriali (ITINERIS 2)
  • MIUR (PON02_00576_3329762/3)
  • Italian Association for Cancer Research (AIRC IG 14368, AIRC MFAG 10520)
  • National Institute of Health (P30CA006973 and UL1 TR 001079)
Topics
  • Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
  • Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
Keywords
EphA2, EGFR, colorectal cancer, ephrin-A1, miR-200a, miR-26b, cetuximab resistance, KRAS wild-type, prognostic factors, gene expression signatures, AOM/DSS model, cell subpopulations, EGFR signaling
MeSH terms
Animals, Disease Models, Animal, Humans, Immunohistochemistry, Male, Models, Biological, Prognosis, Biomarkers, Tumor, Neoplastic Stem Cells, Colorectal Neoplasms, Signal Transduction, Immunophenotyping, Gene Expression Profiling, Receptor, EphA2, Ephrin-A2, Mice, Kaplan-Meier Estimate, Neoplasm Grading, ErbB Receptors

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