AIM: To investigate the role of CD105 in mediating drug resistance to EGFR-targeted therapy in non-small cell lung cancer (NSCLC). METHODS: Imaging mass cytometry was conducted on 66 NSCLC tumors, 44 of which had EGFR mutations. We correlated clinical variables, including overall survival, with CD105 (endoglin) expression, a co-receptor for bone morphogenetic protein (BMP) signaling. Two osimertinib-resistant EGFR-mutant cell lines were developed to study the effects of EGFR and CD105 disruption. Single cell RNA sequencing of the isogenic parental and osimertinib resistant lines was performed. Additionally, ATAC sequencing and Single Cell ENergetIc metabolism by profiling Translation inHibition analysis (SCENITH) was used to assess promoter chromatin status and glycolytic state. RESULTS: We found a negative correlation between CD105 expression and overall survival in patients. Treatment with osimertinib or EGFR knockdown significantly elevated CD105 expression in EGFR-mutant cell lines. Single-cell RNA sequencing identified a subset of cells with heightened endothelial characteristics and altered pyrimidine metabolism, associated with osimertinib resistance. These cells exhibited a slow-cycling behavior, characterized by elevated chromatin condensation and reduced glycolysis. Combining osimertinib with carotuximab, a CD105 neutralizing antibody, significantly reduced the slow-cycling transcriptomic signature, increased chromatin accessibility, and restored glycolysis compared to osimertinib treatment alone. Mass spectrometry confirmed that carotuximab re-engaged EGFR signaling by coupling it with CD105. Consequently, carotuximab re-sensitized resistant tumors to osimertinib by increasing their mitotic index and ERK signaling in mouse models. CONCLUSION: Carotuximab effectively reduced the slow-cycling cell population and restored osimertinib sensitivity, offering a promising strategy for managing refractory NSCLC.