ESAM reduces sensitivity to anti-HER2 therapy in HER2-positive breast cancer by activating the mTOR pathway

Abstract Despite improved survival rates with dual trastuzumab and pertuzumab therapy, patients with HER2-positive breast cancer frequently experience disease progression due to intrinsic or acquired resistance. Elucidating the underlying mechanisms of resistance and identifying actionable therapeutic targets remain urgent clinical priorities. Endothelial cell adhesion molecule (ESAM) is a multifunctional protein implicated in tumor progression; however, its role in insensitivity to anti-HER2 therapy remains poorly understood. In this study, transcriptome sequencing revealed that ESAM is significantly upregulated in HER2-positive breast cancer patient-derived organoids (PDOs) with reduced responsiveness to trastuzumab and pertuzumab. Clinically, elevated ESAM expression correlated with poorer overall survival (OS), relapse-free survival (RFS), and disease-specific survival (DSS). Both in vitro and in vivo functional assays demonstrated that ESAM promotes cell proliferation and attenuates sensitivity to anti-HER2 therapy. Mechanistically, ESAM interacted with Calnexin, reduced its ubiquitination and proteasome-associated degradation, and prolonged its protein half-life, thereby activating mTOR signaling. Importantly, Calnexin depletion in ESAM-overexpressing cells attenuated mTOR activation and restored sensitivity to trastuzumab. Collectively, our findings identify the ESAM/Calnexin/mTOR axis as a candidate biomarker and therapeutic vulnerability in HER2-positive breast cancer.