E‐cadherin is a robust prognostic biomarker in colorectal cancer and low expression is associated with sensitivity to inhibitors of topoisomerase, aurora, and HSP90 in preclinical models

Abstract

Cell–cell and cell–matrix adhesion proteins that have been implicated in colorectal epithelial integrity and epithelial‐to‐mesenchymal transition could be robust prognostic and potential predictive biomarkers for standard and novel therapies. We analyzed in situ protein expression of E‐cadherin (ECAD), integrin β4 (ITGB4), zonula occludens 1 (ZO‐1), and cytokeratins in a single‐hospital series of Norwegian patients with colorectal cancer (CRC) stages I–IV ( n = 922) using multiplex fluorescence‐based immunohistochemistry (mfIHC) on tissue microarrays. Pharmacoproteomic associations were explored in 35 CRC cell lines annotated with drug sensitivity data on > 400 approved and investigational drugs. ECAD, ITGB4, and ZO‐1 were positively associated with survival, while cytokeratins were negatively associated with survival. Only ECAD showed independent prognostic value in multivariable Cox models. Clinical and molecular associations for ECAD were technically validated on a different mfIHC platform, and the prognostic value was validated in another Norwegian series ( n = 798). In preclinical models, low and high ECAD expression differentially associated with sensitivity to topoisomerase, aurora, and HSP90 inhibitors, and EGFR inhibitors. E‐cadherin protein expression is a robust prognostic biomarker with potential clinical utility in CRC.

Abstract

Cell–cell and cell–matrix adhesion proteins have been implicated in colorectal cancer (CRC) progression. Here, we preformed multiplex immunohistochemistry analyses of E‐cadherin (ECAD), zona occludens‐1 (ZO‐1), integrin‐ß4 (ITGB4), and pan‐cytokeratins (PanCK) in two CRC patient series. We identified ECAD as a robust, independent, prognostic biomarker. Low expression of ECAD was associated with low differentiation grade, microsatellite instability, and BRAF mutations. In addition, pharmacoproteomic analyses of CRC cell lines demonstrated that ECAD levels modulated the sensitivity to EGFR, topoisomerase, aurora, and HSP90 inhibitors.