Abstract 4296: The EphA2/EGFR pathway dysregulation associates with poor prognosis and cetuximab treatment response in colorectal cancer
Authors: De Robertis Mariangela , Loiacono Luisa , Fusilli Caterina , Poeta Maria Luana , Mazza Tommaso , Sanchez Massimo , Marchionni Luigi , Signori Emanuela , Lamorte Giuseppe , Vescovi Angelo Luigi , Garcia-Foncillas Jesus , Fazio Vito Michele 
Published: September 2020

Abstract
Tumor heterogeneity and the presence of stem-like cells have been identified as key features for resistance to anticancer treatments including targeted therapy. The Eph receptors comprise a large family of receptor tyrosine kinases that marks stem-like cells in different tissues. In colorectal cancer (CRC), EphA2 receptor overexpression has been linked to stem-like properties of cells and malignancy. In particular, EphA2 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. We investigated the molecular crosstalk and miRNAs modulation of the EphA2 and EGFR pathways in CRC. We also explored the role of EphA2/EGFR pathway mediators as prognostic factors or predictors of cetuximab benefit in CRC patients. We used a strategy to uncover in murine homogeneous tumor EphA2high cells a novel potential molecular signature involving EphA2 and EGFR pathways. Gene expression analysis was performed in EphA2high cells isolated from colorectal adenocarcinoma obtained from the AOM/DSS-induced CRC murine model. Six independent cohorts of patients were analyzed to determine the potential prognostic role of a EphA2/EGFR signature and its effect on cetuximab treatment response. We identified a gene expression pattern, including a coherent miRNAs dysregulation, reflecting the activation of EphA2 and EGFR pathways. 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. Furthermore, EphA2 and EGFR overexpression showed a combined effect relative to cetuximab resistance, independently from KRAS mutation status. Collectively, our data indicate that EphA2/Efna1/EGFR genes, linked to a possible control by miRNAs, could be proposed as novel prognostic biomarkers in CRC. Moreover, EphA2 could be linked to a mechanism of resistance to cetuximab alternative to KRAS mutations. Since cetuximab resistance, associated to an intrinsic genetic heterogeneity, remains the most critical issue in treating CRC, this study sheds light on new potential biomarkers and therapeutically actionable kinase targets in the EphA2/EGFR-linked pathway.
Citation Format: Mariangela De Robertis, Luisa Loiacono, Caterina Fusilli, Maria Luana Poeta, Tommaso Mazza, Massimo Sanchez, Luigi Marchionni, Emanuela Signori, Giuseppe Lamorte, Angelo Luigi Vescovi, Jesus Garcia-Foncillas, Vito Michele Fazio. The EphA2/EGFR pathway dysregulation associates with poor prognosis and cetuximab treatment response in colorectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4296.