The EphB2-MYC Axis is a Major Determinant of Barrett’s Pathobiology and a Therapeutic Vulnerability in Esophageal Cancer

ABSTRACT Esophageal adenocarcinoma (EAC), a highly aggressive cancer with limited therapeutic options, often arises in the backdrop of a molecularly-complex esophageal metaplasia disorder, Barrett’s Esophagus (BE). Using transcriptomics and systems biology analyses of treatment-naïve malignant/pre-malignant biopsy tissues, we found Eph receptor B2 (EphB2) tyrosine kinase signaling to be frequently hyperactivated during early stages of EAC development, and across the BE-EAC continuum. Functional studies revealed EphB2 to be an upstream post-translational regulator of c-MYC activity and as a key molecular dependency in BE/EAC. Single-cell transcriptomics in a porcine esophageal 3D spheroid model showed enhanced EphB2 and MYC activity to be significantly associated with BE-like cell fate. shRNA-based knockdown of EphB2 or small molecule inhibitors of MEK, that modulate MYC protein stability, proved effective in suppressing EAC tumor growth in vivo . These findings point to EphB2-MYC axis as an early promoter of EAC and a novel therapeutic vulnerability in this increasingly-prevalent esophageal malignancy. STATEMENT OF SIGNIFICANCE We identify EphB2 signaling as a potential master regulator and early promoter of esophageal adenocarcinoma, and the proto-oncogene MYC as a key downstream effector of EphB2 function. Targeting the EphB2-MYC axis could be a promising therapeutic strategy for these often refractory and lethal EAC tumors.