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

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 crosstalk and microRNAs 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 CRC patients. Experimental Design Gene expression analysis was performed in EphA2high cells isolated from CRC of 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, Atf2) reflecting the activation of EphA2 and EGFR pathways and a coherent dysregulation of mir-26b and mir-200a. Such pattern showed prognostic significance in stage I-III CRC patients, 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.

Emerging and Diverse Functions of the EphA2 Noncanonical Pathway in Cancer Progression

“…De Robertis et al reported that colon adenocarcinoma cells with high EphA2 expression levels isolated from the AOM/DSS mouse model showed higher levels of stem cell markers and lower levels of differentiation markers than the low-EphA2 population. 31) At the same time, ephrin-A1 was decreased in the high-EphA2 population, suggesting that the noncanonical pathway is responsible for cancer stemness properties. Miao et al reported that the Akt-EphA2 pathway is essential for glioblastoma CSC invasion and self-renewal.…”

“…41) Many reports showed that patients with low ephrin-A1 expression had a poor prognosis, suggesting the existence of EphA2 tyrosine kinase-independent regulation. 31,42,43) Thirty-seven phosphorylation sites are identified within the intracellular domain of EphA2 in the PhosphoSitePlus database. 44) Among them, 25 phosphorylation sites are serine and threonine residues.…”

“…Resistance to Molecular-Targeted Agents EphA2 has been reported to be involved in acquired resistance to EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib, afatinib, or EGFR monoclonal antibodies. [27][28][29][30][31][32] For example, Koch et al 30) demonstrated that EphA2 was overexpressed in gefitinib-resistant NSCLC, and the multikinase inhibitor dasatinib overcame the resistance, suggesting the involvement of the EphA2 noncanonical pathway via Akt or RSK. Patients with colorectal cancer with wild-type KRAS are often treated with the EGFR monoclonal antibody cetuximab.…”

“…[23][24][25][26] Moreover, EphA2 has been reported to engage in cross-talk with other RTK family members to promote tumor malignancy. [27][28][29][30][31][32] For example, it is involved in the resistance to ErbB tyrosine kinase inhibitor (TKI) or monoclonal antibodies, and EphA2 inhibition could become a new strategy to restore anti-ErbB sensitivity. Hence, many reports identified EphA2 as a critical tumorigenic and tumor-promoting factor.…”

The Role of Escherichia coli in the Development and Progression of Cancer

“…This cellular mechanism is related to the development of colon cancer (70,71), and up regulation of EGFR has been correlated with a poor prognosis in colon cancer patients (72). Although the mechanism by which EPEC induces EGFR phosphorylation is not entirely clear, it has been showed that translocation of effectors EspF and EspZ could be associated with EGFR phosphorylation (73).…”