Targeting the EpCAM ‐ AXL axis to overcome drug resistance in lung cancer

Drug resistance significantly limits the long‐term effectiveness of targeted therapies in lung cancer. AXL, a receptor tyrosine kinase (RTK), is a well‐established driver of drug resistance in many cancers, including lung cancer. Epithelial cell adhesion molecule (EpCAM), which is commonly overexpressed in epithelial cancers, is also a critical signaling molecule. In this study, we elucidated the role of EpCAM in drug resistance and its mechanistic association with AXL. We found that soluble epithelial cell adhesion molecule (sEpCAM) expression robustly enhanced hallmark cancer phenotypes and promoted pro‐survival functions by upregulating AXL expression. Gene expression and pathway analyses further identified significant alterations in core cancer signaling pathways, including NF‐kB, STAT3, AKT, and ERK. The ectopic expression of sEpCAM concurrently upregulated endogenous EpCAM expression in the tumor environment. Functionally, sEpCAM confers broad resistance to conventional chemotherapy. Drug sensitivity assays revealed that proteasome inhibition effectively reversed the sEpCAM‐induced drug resistance by reducing AXL protein levels. Translational analysis of the lung cancer patient cohort data indicated that patients with aggressive disease co‐expressing EpCAM and AXL may be particularly amenable to proteasome‐based therapy. Characterization of the EpCAM‐AXL axis gene signature further uncovered connections to p53, integrin, and Rho GTPase signaling as well as an intriguing link to tumor immune evasion. Our findings suggest that EpCAM‐AXL co‐expression in a subset of patients with lung cancer serves as both a predictive biomarker and a promising therapeutic target to counteract treatment failure.