GPNMB-ECD drives acquired resistance to osimertinib in NSCLC via inducing tumor cell cytoskeletal reorganization

BACKGROUND: Acquired resistance constitutes a major obstacle to the efficacy of osimertinib therapy in nonsmall-cell lung cancer (NSCLC), yet its underlying mechanisms remain incompletely understood. While the soluble extracellular domain of GPNMB (GPNMB-ECD) is recognized as a driver of tumor progression, its involvement in acquired resistance to osimertinib remains unknown. PURPOSE: This study aimed to investigate the role of GPNMB-ECD in acquired osimertinib resistance in NSCLC. METHODS: The expression dynamics of GPNMB in osimertinib-sensitive (OS) and osimertinib-resistant (OR) NSCLC tissues and cell lines were profiled using single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq, respectively. Full-length GPNMB and GPNMB-ECD levels in tumor tissues and patient plasma were assessed by immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA). In vitro, the impact of GPNMB-ECD on osimertinib sensitivity was evaluated using CCK-8, colony formation, flow cytometry, and transwell assays. Correspondingly, in vivo effects were investigated in nude mouse models of subcutaneous and pulmonary metastasis. The underlying mechanisms were explored through co-immunoprecipitation (Co-IP), immunofluorescence, and transmission electron microscopy (TEM). Finally, the therapeutic efficacy of the anti-GPNMB-ECD antibody was evaluated in humanized patient-derived xenograft (huPDX) models. RESULTS: Tumor cells exhibited elevated GPNMB expression in OR tissues compared with OS controls and emerged as the primary source of GPNMB-ECD within the OR TME. Plasma levels of GPNMB-ECD were substantially higher in patients with OR NSCLC compared with patients with OS NSCLC, suggesting this marker as a potential indicator of acquired resistance and poor prognosis. Functional studies confirmed that GPNMB-ECD promotes osimertinib resistance both in vitro and in vivo. Mechanistically, GPNMB-ECD engages syndecan-4 (SDC4) on tumor cells, triggering SDC4 phosphorylation, F-actin reorganization, and Yes-associated protein (YAP) nuclear translocation, thereby upregulating pro-tumorigenic genes and reducing osimertinib sensitivity. Crucially, anti-GPNMB-ECD antibodies restored osimertinib sensitivity in huPDX models established from human NSCLC tumors. CONCLUSIONS: Our findings define GPNMB-ECD-driven resistance as a novel paradigm in NSCLC and identify a viable precision therapeutic strategy to overcome it.