Definition of a Novel Cuproptosis-Relevant lncRNA Signature for Uncovering Distinct Survival, Genomic Alterations, and Treatment Implications in Lung Adenocarcinoma

Abstract

Objective. Cuproptosis is a newly discovered copper-independent cell death modality, and limited evidence suggests the critical implications in human cancers. Nonetheless, the clinical impacts of cuproptosis-relevant lncRNAs in lung adenocarcinoma (LUAD) remain largely ill-defined. The present study was aimed at defining a cuproptosis-relevant lncRNA signature for LUAD and discuss the clinical utility. Methods. We collected transcriptome expression profiling, clinical information, somatic mutation, and copy number variations from TCGA-LUAD cohort retrospectively. The genetic alterations of cuproptosis genes were systematically assessed across LUAD, and cuproptosis-relevant lncRNAs were screened for defining a LASSO prognostic model. Genomic alterations, immunological and stemness features, and therapeutic sensitivity were studied with a series of computational approaches. Results. Cuproptosis genes displayed aberrant expression and widespread genomic alterations across LUAD, potentially modulated by m6A/m5C/m1A RNA modification mechanisms. We defined a cuproptosis-relevant lncRNA signature, with a reliable efficacy in predicting clinical outcomes. High-risk subset displayed higher somatic mutations, CNVs, TMB, SNV neoantigens, aneuploidy score, CTA score, homologous recombination defects, and intratumor heterogeneity, cytolytic activity, CD8+ T effector, and antigen processing machinery, proving that this subset might benefit from immunotherapy. Increased stemness indexes and activity of oncogenic pathways might contribute to undesirable prognostic outcomes for high-risk subset. Additionally, high-risk patients generally exhibited higher response to chemotherapeutic agents (cisplatin, etc.). We also predicted several small molecule compounds (GSK461364, KX2-391, etc.) for treating this subset. Conclusion. Accordingly, this cuproptosis-relevant lncRNA signature offers an efficient approach to identify and characterize diverse prognosis, genomic alterations, and treatment outcomes in LUAD, thus potentially assisting personalized therapy.

Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research

“…However, the use of ICIs is restricted by the lack of tumor-associated antigens, which results in more than two thirds of the patients to not react to ICI-based monotherapy [169]. However, due to the intricate role of the novel RCD modes in TME, we [169,336,337], and possibly cuproptosis [338]. Like what we mentioned, the novel RCDs in TME seriously activate proinflammatory cytokines, infiltration of cytotoxic T cells, and other lymphocytes, which are significant for the sensitivity of various tumors to ICIs [176].…”

Prognostic and immunotherapeutic implications of bilirubin metabolism‐associated genes in lung adenocarcinoma

“…Additionally, genes including EIF2AK3, LBR and SLC2A1 demonstrated significant correlations with HRD, intimating a potential association with the DNA damage response pathway in LUAD (Figure 5E). This observation, alongside other studies highlighting HRD and chromosomal instability's roles in LUAD progression, 36,37 underscores the complex molecular underpinnings of this cancer type, offering novel insights for targeted therapeutic strategies.…”

Implications of GCLC in prognosis and immunity of lung adenocarcinoma and multi-omics regulation mechanisms

“…LUAD is an extremely heterogeneous malignancy that involves complex crosstalk of malignant cells with tumor microenvironment [ 23 , 24 ]. Immune cells dominate the tumor microenvironment, which nearly affect each stage of tumorigenesis via direct interactions with malignant cells [ 25 ].…”