bims-meluca 2026-07-26 papers

Transl Oncol. 2026 Jul 20. pii: S1936-5233(26)00252-4. [Epub ahead of print]71 102915

SMARCA4, STK11, and KEAP1 co-inactivation associates with poor prognosis and upregulation of the TGF-β pathway in lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD) is clinically and molecularly defined by oncogenic driver mutations, identification of which has led to the development of driver-targeted therapies and substantial improvements in prognosis for subsets of LUAD patients. Recent studies assessing clinical outcomes in the context of multigenic alterations have identified secondary mutations that might explain differential responses to targeted therapies, chemotherapies and immunotherapies. Genetic inactivation or loss of SMARCA4, which frequently co-occurs with loss-of-function mutations in STK11 and KEAP1, is especially predictive of poor prognosis and shorter overall survival in LUAD patients, regardless of driver status. We sought to examine the clinical and functional associations of SMARCA4 deficiency in LUAD, with or without co-associated STK11/KEAP1 loss-of-function.
METHODS: We examined correlation between SMARCA4 loss, gene expression and prognosis through genomic and transcriptomic profiling of clinically annotated LUAD samples. We generated isogenic cell line models with genetic knockouts of SMARCA4 with or without concomitant STK11 and KEAP1 to profile mutationally-defined genotypes of interest in vitro and in vivo. Lastly, we interrogated the functional dependency of SMARCA4/STK11/KEAP1 triple mutant models on TGF-β signaling to assess its potential as a therapeutic target.
RESULTS: SMARCA4/STK11/KEAP1 triple mutant LUAD is associated with poor survival and high frequency of multisite metastasis. SMARCA4/STK11/KEAP1 triple knockout models showed enhanced migration and invasion in vitro, and diversified organotropism in an in vivo intracardiac xenograft metastasis assay. RNA-Seq and DNaseI-Seq of these in vitro models and clinical samples identified upregulation of TGF-β signaling and EMT gene expression signatures, and corresponding changes in chromatin accessibility, in SMARCA4/STK11/KEAP1 triple mutant LUAD.
CONCLUSIONS: We identify SMARCA4/STK11/KEAP1 triple mutant LUAD as a prognostically significant disease subset and nominate TGF-β signaling as a potential therapeutic target.

Keywords: Clinicogenomics; Keap1; Lung adenocarcinoma (luad); Metastasis; Smarca4; Stk11; TGF-β

DOI: https://doi.org/10.1016/j.tranon.2026.102915

Discov Oncol. 2026 Jul 19.

Integrated multi-omics and SHAP analysis reveal the core mechanisms of metabolic reprogramming in lung adenocarcinoma.

Yuqing Huang, Chaojie Wang, Zhihao Zhang, Yandan Shi, Peng Lei.

Metabolic reprogramming is a pivotal hallmark of the malignant progression of lung adenocarcinoma (LUAD), yet its core regulatory genes and underlying molecular mechanisms remain largely elusive. In this study, we systematically deciphered the core regulatory network of LUAD metabolic reprogramming by integrating multi-omics analysis with the SHAP (SHapley Additive exPlanations) algorithm. Initially, LUAD transcriptomic and clinical data were acquired from the TCGA and GEO databases. Combined with 703 metabolic reprogramming-related genes retrieved from the Genecards database, 40 differentially expressed genes were identified via differential analysis, and key genes significantly impacting patient survival were subsequently isolated through prognostic analysis. Utilizing SHAP analysis to quantify the specific prognostic contributions of these genes, GPI, PFKP, and LDHB were recognized as the core regulatory genes. Single-cell sequencing analysis revealed that these three genes are highly expressed in the epithelial cells of LUAD tumor tissues and are closely associated with immune cell infiltration. In vitro cellular functional assays confirmed that silencing GPI, PFKP, or LDHB significantly restrained the proliferation and invasion capabilities of A549 cells, whilst regulating glucose metabolism and lactate production. Virtual knockout experiments further unraveled the downstream signaling pathway networks orchestrated by these three genes. Through combined multi-omics and SHAP analysis, this study elucidates, for the first time, the central roles of GPI, PFKP, and LDHB in the metabolic reprogramming of LUAD, providing a novel theoretical foundation for the development of diagnostic biomarkers and targeted therapeutics.

Keywords: GPI; LDHB; Lung adenocarcinoma; Metabolic reprogramming; Multi-omics analysis; PFKP; SHAP algorithm

DOI: https://doi.org/10.1007/s12672-026-05588-8

Oncol Res. 2026 ;34(8): 26

GPX4 Defines an Immune-Cold Phenotype and Poor Prognosis in Resected Lung Adenocarcinoma.

Ganxin Wang, Zhongan Liu, Tian Zhou, Boting Yang, Jiaqin Chen, Jing Chen, Kai Huang, Yunqing Xu, Quan Tang, Xiangqian Yin, Guangqin Xiao, Sijia Zhang.

Objectives: Ferroptosis resistance may contribute to tumor progression and immune escape. This study evaluated the prognostic and immunological significance of glutathione peroxidase 4 (GPX4), a core ferroptosis-suppressive enzyme, in surgically resected lung adenocarcinoma. Methods: We retrospectively analyzed 104 patients with primary lung adenocarcinoma who underwent curative resection. GPX4 protein expression was assessed by immunohistochemistry (IHC) using the histological score (H-score), and patients were classified as GPX4-low (n = 54) or GPX4-high (n = 50). Intratumoral immune contexture was quantified using CD3, CD4, CD8, CD68, programmed cell death protein 1 (PD-1), and programmed death-ligand 1 (PD-L1) staining. Disease-free survival (DFS) and overall survival (OS) were analyzed using Cox regression. Cutoff sensitivity analyses, category consolidation, ridge-penalized Cox regression, events-per-variable assessment, bootstrap internal validation, and interobserver reproducibility testing were performed to strengthen statistical robustness. Results: GPX4-high tumors were associated with systemic inflammatory and immune-related features, including elevated fibrinogen (p = 0.015), lower lymphocyte-to-monocyte ratio (p = 0.003), and altered aspartate aminotransferase-to-alanine aminotransferase ratio (p = 0.028). GPX4-high tumors showed reduced intratumoral CD3+, CD4+, CD8+, and CD68+ immune-cell infiltration, together with increased PD-1 and PD-L1 expression, indicating an immune-cold yet checkpoint-enriched phenotype. After category consolidation and ridge-penalized multivariable adjustment, high GPX4 expression remained independently associated with worse DFS (HR, 8.63; 95% CI, 2.99-24.91; p < 0.001) and OS (HR, 6.94; 95% CI, 2.44-19.74; p < 0.001). GPX4-based prognostic models showed bias-corrected C-index values of 0.782 for DFS and 0.826 for OS, with calibration slopes of 0.964 and 0.937, respectively. Conclusions: High GPX4 expression identifies a clinically adverse, ferroptosis-resistant, immune-remodeled phenotype in resected lung adenocarcinoma. Integrating GPX4 with clinicopathological and inflammatory variables may improve postoperative risk stratification.

Keywords: GPX4; Lung adenocarcinoma; PD-L1; nomogram; tumor immune microenvironment

DOI: https://doi.org/10.32604/or.2026.083840

Cell Signal. 2026 Jul 23. pii: S0898-6568(26)00407-9. [Epub ahead of print] 112750

Targeting the adaptor protein Gab1 overcomes MET/Src-driven alectinib resistance in ALK-rearranged NSCLC.

Hengyi Chen, Caiyu Lin, Chen Hu, Wenwen Li, Yong He.

BACKGROUND: In non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) rearrangement, bypass signaling activation commonly leads to resistance against alectinib. Identifying key molecular targets that integrate signals from resistance-driving kinases is crucial for overcoming this resistance. However, these targets have not yet been identified.
METHODS: We generated alectinib-resistant (AR) subclones from H3122 and H2228 cells. Subsequently, we analyzed bypass signaling pathways using western blotting, evaluated drug sensitivity with Cell Counting Kit-8 (CCK-8) assays. To assess the function of Grb2-associated binder 1 (Gab1), we employed siRNA-mediated knockdown and lentiviral shRNA both in vitro and in xenograft models. Additionally, we determined the stability of Gab1 through cycloheximide chase assays.
RESULTS: AR cells demonstrated concurrent activation of the mesenchymal epithelial transition receptor tyrosine kinase (MET) and Rous sarcoma oncogene cellular homolog non-receptor tyrosine kinase (Src), accompanied by upregulation of Gab1. The combined inhibition of MET and Src, as opposed to single-agent blockade, effectively suppressed Gab1/protein kinase B (AKT) signaling and restored sensitivity to alectinib. Gab1 knockdown mirrored the effects of dual kinase inhibition, by disrupting MET/Src/AKT signaling and resensitizing cells to alectinib. Mechanistically, the elevation of Gab1 resulted from post - translational stabilization, with a significantly extended half - life in resistant cells. In vivo, silencing Gab1 inhibited the growth of H3122-AR2 xenografts without causing systemic toxicity, which correlated with decreased phosphorylation of MET, Src and AKT in tumor tissues.
CONCLUSION: In ALK-positive NSCLC with acquired resistance to alectinib, Gab1 emerged as a crucial downstream signaling convergence target of MET and Src co-activation. Targeting this adaptor protein presented a promising therapeutic strategy to overcome bypass-mediated resistance.

Keywords: ALK-positive NSCLC; Alectinib resistance; Gab1; MET; Src

DOI: https://doi.org/10.1016/j.cellsig.2026.112750