Work

A novel mouse cell line model reveals the tumor intrinsic and immune characteristics of EGFR-mutant lung cancer

Year: 2025

Type: article

Abstract: Background: Epidermal growth factor receptor (EGFR) mutations are the primary oncogenic driver and therapeutic target of lung adenocarcinoma (LUAD), yet how they reshape the tumor microenvironment remains large unclear. The lack of highly efficient immunocompetent models that recapitulate both the genetic and immunologic features of EGFR-mutant LUAD impedes the elucidation of immune evasion mechanisms.Methods: EGFR mutant and p53 deficient (EP) cell lines were established from a genetically engineered mouse model (GEMM). These cell lines were used to generate orthotopic tumors in immunocompetent mice. Drug sensitivity assays were conducted to evaluate responses to Osimertinib, the EGFR tyrosine receptor kinase inhibitor (TKI). Multi-omics analyses, including transcriptomic, metabolic profiling and multiplex flow cytometry, were performed in both mouse models and human LUAD cohort to elucidate the characteristics of tumor microenvironment in EGFR-mutant LUAD.Findings: EP cell lines formed tumors in immunocompetent mice and exhibited Osimertinib sensitivity . EP tumors effectively simulated acquired resistance to EGFR-TKI therapy, demonstrating transcriptional reprogramming characterized by enhanced epithelial-mesenchymal transition and Wnt-β-catenin signaling. Multi-omics analyses of EP tumors revealed previously undefined molecular features of human EGFR-mutant LUAD, with distinct transcriptomic and metabolic profiles compared to KRAS-mutant models. Immune profiling showed compromised adaptive immunity in EP tumors, including reduced infiltration of tissue-resident memory T cell and increased M2-like macrophage polarization.Interpretation: EP models enable the discovery of new mechanisms underlying TKI resistance and immune evasion in EGFR mutant LUAD, offering a valuable tool for developing innovative therapeutic strategies.

Source: Theranostics

DOI: 10.7150/thno.118234