CAF-mediated compartmentalized dual POSTN–ITGB8 axis drives Osimertinib resistance in lung adenocarcinoma

作者：Jiaming Cao, Yibing Liu, Junting Chen, Xuelian Li, Zhihua Yin, Xiaoxia Xue, Bonan Chen, Baosen Zhou, Chang Zheng · 发表于：Journal of Pharmaceutical Analysis · 年份：2026 · DOI：10.1016/j.jpha.2026.101689 · 研究领域：Lung Cancer Treatments and Mutations、Fibroblast Growth Factor Research、Melanoma and MAPK Pathways

Lung adenocarcinoma (LUAD) represents a histological subtype of lung cancer with substantial disease burden. A particularly prominent feature in Asian populations is the exceptionally high incidence of epidermal growth factor receptor (EGFR) mutations. For EGFR-mutant LUAD, Osimertinib therapy faces the nearly inevitable development of acquired resistance, and its underlying mechanisms remain incompletely understood. By integrating clinical data, organoid models, and single-cell RNA sequencing (scRNA-seq), we confirmed that integrin subunit beta 8 (ITGB8) was highly expressed in LUAD and strongly correlates with poor prognosis and reduced response to Osimertinib. ScRNA-seq analysis revealed a dominant paracrine axis between ITGB8 + cancer cells and POSTN-expressing cancer-associated fibroblasts (POSTN + CAFs). Employing extensive in vitro and in vivo approaches, we established that CAF-derived POSTN drives LUAD malignancy and acquires resistance via a novel compartmentalized dual mechanism. This dual mechanism involves exosomal POSTN being internalized by ITGB8 + cancer cells, where it directly binds to and activates mechanistic target of rapamycin (mTOR) signaling. In parallel, secreted POSTN engages the cell surface ITGB8 receptor to initiate the canonical focal adhesion kinase (FAK)/proto-oncogene tyrosine-protein kinase Src (Src)/protein kinase B (AKT) signaling cascade. Consequently, targeting the POSTN-ITGB8 axis effectively suppresses tumor growth and metastasis, and r...