A Zinc Finger Protein-Based Prognostic Model in Lung Adenocarcinoma Identifies FGD3 as a Marker Associated with Lorlatinib Resistance

Background: Lung adenocarcinoma (LUAD) is the most common type of lung cancer and a major cause of cancer death. Zinc finger proteins (ZNFs) have been implicated in LUAD progression, functioning either as oncogenes or tumor suppressors. Therefore, an in-depth investigation of ZNFs may contribute to the development of novel diagnostic and therapeutic strategies for LUAD. Methods: Transcriptomic and clinical data were obtained from the TCGA and GEO databases. Prognosis-related ZNF genes were identified using univariate Cox, LASSO, and multivariate Cox regression analyses. An eight-gene ZNF-based prognostic signature was constructed and validated in two independent external cohorts (GSE50081 and GSE26939). A nomogram integrating independent prognostic factors was developed. Immune infiltration, somatic mutation profiles, and drug sensitivity were systematically analyzed. We further focused on FGD3, a key gene from the signature, examining its expression in LUAD cells and tissues, including lorlatinib-resistant models. Results: The prognostic signature comprising TRIM6, TRIM29, CTCFL, FGD3, GATA4, CASZ1, TRAF2, and ZNF322 effectively stratified patients into distinct risk groups with significantly different overall survival (p < 0.05). The risk score, together with T and N stage, served as independent prognostic predictors (n = 500, p < 0.05). High-risk patients exhibited an immune-desert phenotype, increased tumor mutational burden, and distinct drug sensitivity patterns. Notably, FGD3 expression was downregulated in LUAD tissues (n = 14, p < 0.0001) and lorlatinib-resistant cells, and its restoration suppressed resistant cell proliferation and partially reversed drug resistance. Conclusions: This study establishes a promising ZNF-based prognostic model for LUAD, providing a potential tool for risk stratification and individualized therapeutic decision-making. The identification of FGD3 as a potential mediator of drug resistance highlights its promise as a candidate biomarker and therapeutic target in LUAD.