Lung Adenocarcinoma Therapy Research Articles

The pro-tumor activity of INTS7 on lung adenocarcinoma via inhibiting immune infiltration and activating p38MAPK pathway

Lung adenocarcinoma (LUAD) is the most common lung cancer, accounting for 19.4% of all cancer deaths. Our previous study discovered that INTS7 expression was upregulated in LUAD, while the precise mechanism by which INTS7 exerts pro-cancer effects remains unknown. In our study, shRNA was used to knockdown the expression of INTS7 in A549 cells. Cancer behaviors in vitro were determined by CCK8 and transwell assays. Xenograft mice models were constructed to detect the tumorigenesis in vivo. Immunofluorescence and toluidine blue staining were used to test the immune infiltration. Bioinformatics analysis was adopted to predict the potential signaling pathways and construct INTS7-derived genomic prognostic model. Western blot was utilized to confirm the molecular pathways. In total, downregulation of INTS7 suppressed proliferation, invasion and migration of A549 cells, as well as tumor growth. Bioinformatics and western blot analysis indicated that p38MAPK pathway participated in the regulatory mechanism of INTS7. Moreover, INTS7 expression was negatively correlated with infiltration of memory B cells and mast cells, while positively correlated with infiltration of macrophages M2. A nomogram, including INTS7-derived risk score, was used to estimate individual’s survival probability. Generally, our findings provided comprehensive understanding of the molecular mechanisms about INTS7, and targeting INTS7 may represent a potential therapy for LUAD.

Comprehensive multi-omics integration uncovers mitochondrial gene signatures for prognosis and personalized therapy in lung adenocarcinoma

The therapeutic efficacy of lung adenocarcinoma (LUAD), the most prevalent histological subtype of primary lung cancer, remains inadequate, with accurate prognostic assessment posing significant challenges. This study sought to elucidate the prognostic significance of mitochondrial-related genes in LUAD through an integrative multi-omics approach, aimed at developing personalized therapeutic strategies. Utilizing transcriptomic and single-cell RNA sequencing (scRNA-seq) data, alongside clinical information from publicly available databases, we first applied dimensionality reduction and clustering techniques to the LUAD single-cell dataset, focusing on the subclassification of fibroblasts, epithelial cells, and T cells. Mitochondrial-related prognostic genes were subsequently identified using TCGA-LUAD data, and LUAD cases were stratified into distinct molecular subtypes through consensus clustering, allowing for the exploration of gene expression profiles and clinical feature distributions across subtypes. By leveraging an ensemble of machine learning algorithms, we developed an Artificial Intelligence-Derived Prognostic Signature (AIDPS) model based on mitochondrial-related genes and validated its prognostic accuracy across multiple independent datasets. The AIDPS model demonstrated robust predictive power for LUAD patient outcomes, revealing significant differences in responses to immunotherapy and chemotherapy, as well as survival outcomes between risk groups. Furthermore, we conducted comprehensive analyses of tumor mutation burden (TMB), immune microenvironment characteristics, and genome-wide association study (GWAS) data, providing additional insights into the mechanistic roles of mitochondrial-related genes in LUAD pathogenesis. This study not only offers a novel approach to improving prognostic assessments in LUAD but also establishes a strong foundation for the development of personalized therapeutic interventions.

MAZ promotes tumor proliferation and immune evasion in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is the most dominant histological subtype of lung cancer and one of the most lethal malignancies. The identification of novel therapeutic targets is required for the treatment of LUAD. Here, we showed that MYC-associated zinc-finger protein (MAZ) is upregulated in LUAD tissues. MAZ expression levels are inversely correlated with patient survival. Silencing of MAZ decreased tumor proliferation and the expression of pro-tumorigenic chemokines and Galectin-9 (Gal-9), an immune checkpoint molecule. The pro-tumorigenic chemokines and Gal-9 induce immune suppression by recruitment of myeloid cells and inhibition of T cell activation, respectively. Mechanistically, MAZ transcriptionally regulates KRAS expression and activates its downstream AKT-NF-κB signaling pathway, which is crucial for tumor progression and immune evasion. Additionally, in vivo animal models and bioinformatic analyses indicated that MAZ suppression could enhance the efficacy of immune checkpoint blockade (ICB) therapy for LUAD. Overall, our results suggest that MAZ plays an important role in regulating cell proliferation and immune evasion via KRAS/AKT/NF-κB signaling in LUAD. Our findings offer a candidate molecular target for LUAD therapy, with implications for improving the efficacy of ICB therapy.

Taiwan Nationwide Study of First-Line ALK-TKI Therapy in ALK-Positive Lung Adenocarcinoma.

The clinical outcomes of patients with anaplastic lymphoma kinase-positive (ALK+) advanced lung adenocarcinoma vary according to real-world data. In this study, we aimed to investigate the treatment discontinuation (TTD) and overall survival (OS) of patients with ALK+ advanced lung adenocarcinoma treated with first-line ALK-TKIs in Taiwan. This retrospective study evaluated all advanced lung adenocarcinoma patients registered in the National Taiwan Cancer Registry from 2017 to 2020 who had ALK rearrangement and received ALK-TKI treatment, using data from Taiwan's National Health Insurance Research Database (NHIRD). The TKI treatment sequences were classified into first generation (G1: crizotinib), second generation (G2: ceritinib, alectinib, brigatinib), and third generation (G3: lorlatinib). A total of 587 patients were analyzed, with a median age of 60.0 years, 91 (15.5%) aged ≥ 74 years, 293 (49.9%) female, 397 (67.6%) never smoked, and 534 (91.0%) with stage IV disease. Patients who received next-generation ALK-TKIs during the treatment course had longer median time to ALK-TKI TTD and OS. The TTD of the G1, G1+2, G1+2+3, G2, and G2+3 groups was 7.5 (5.4-11.1), 40.6 (29.4-not calculated (NC)), 50.3 (41.3-NC), 34.3 (29.2-43.0), and 36.3 (22.4-NC) months, respectively (p < 0.001). The median OS of the patients in the G1, G1+2, G1+2+3, G2, and G2+3 groups was 10.6 (7.5-14.6), not reached (NR) (NC-NC), NR (NC-NC), 43.0 (36.3-NC), and NR (30.3-NC) months, respectively (p < 0.001). Compared with treatment with crizotinib alone, the multivariate analysis revealed that treatment with next-generation TKIs was independently associated with longer TTD (G1+2 (hazard ratio (HR), 0.24; 95% CI 0.17-0.33; p < 0.001), G1+2+3 or G1+3 (HR, 0.17; 95% confidence interval (CI), 0.10-0.28; p < 0.001), G2 (HR, 0.26; 95% CI 0.19-0.36; p < 0.001), and G2+3 (HR, 0.25; 95% CI 0.14-0.44; p < 0.001)) and median OS (G12 (HR, 0.24; 95% CI 0.17-0.35; p < 0.001), G1+2+3 or G1+3 (HR, 0.09; 95% CI 0.04-0.21; p < 0.001), G2 (HR, 0.22; 95% CI 0.15-0.31; p < 0.001), and G2+3 (HR, 0.20; 95% CI 0.10-0.42; p < 0.001)). For patients with ALK+ NSCLC, treatments including next-generation ALK-TKIs were independently associated with longer survival outcomes.

Multicenter cohort analysis of anoikis and EMT: implications for prognosis and therapy in lung adenocarcinoma

BackgroundAnoikis and epithelial-mesenchymal transition (EMT) are pivotal in the distant metastasis of lung adenocarcinoma (LUAD). A detailed understanding of their interplay and the identification of key genes is vital for effective therapeutic strategies against LUAD metastasis.MethodsKey prognostic genes related to anoikis and EMT were identified through univariate Cox regression analysis. We utilized ten machine learning algorithms to develop the Anoikis and EMT-Related Optimal Model (AEOM). The TCGA-LUAD dataset served as the training cohort, while six additional international multicenter LUAD datasets were employed as validation cohorts. The average concordance index (c-index) was used to evaluate model performance and identify the most effective model. Subsequent multi-omics analyses were conducted to explore differences in pathway enrichment, immune infiltration, and mutation landscapes between high and low AEOM groups. Experimental validation demonstrated that RHPN2, a key biomarker within the model, acts as an oncogene facilitating LUAD progression.ResultsThe AEOM displayed superior prognostic predictive performance for LUAD patients, outperforming numerous previously published LUAD signatures. Biologically, the AEOM was notably associated with immune features; the high AEOM group exhibited decreased immune activity and a tendency towards immune-cold tumors, as well as a higher tumor mutational burden (TMB). Subgroup analysis revealed that the low AEOM + high TMB group had the most favorable prognosis. The high AEOM group was primarily enriched in cell cycle-related pathways, promoting cancer cell proliferation. RHPN2, a crucial gene within the AEOM (correlation = 0.85, P < 0.05), was linked to poorer prognosis in LUAD patients with elevated RHPN2 expression. Further in vitro experiments showed that RHPN2 modulates LUAD cell proliferation and invasion.ConclusionThe AEOM provides a robust prognostic model for LUAD, uncovering critical immune and biological pathways, with RHPN2 identified as a key oncogenic driver. These findings offer valuable insights for targeted therapies and enhanced patient outcomes.

METTL14-mediated m6A mRNA modification of G6PD promotes lung adenocarcinoma

METTL14 functions as an RNA methyltransferase involved in m6A modification, influencing mRNA biogenesis, decay, and translation processes. However, the specific mechanism by which METTL14 regulates glucose-6-phosphate dehydrogenase (G6PD) to promote the progression of lung adenocarcinoma (LUAD) is not well understood. Quantitative measurement and immunohistochemistry (IHC) analysis have demonstrated higher levels of m6A in LUAD tissues compared to adjacent normal tissues. Additionally, the expression of METTL14 was significantly increased in LUAD tissues. In LUAD cell lines, both METTL14 and m6A levels were elevated compared to normal human lung epithelial cells. Knockdown of METTL14 markedly reduced LUAD cell proliferation, migration, and invasion. Conversely, overexpression of METTL14, but not the mutant form, significantly enhanced these cellular processes in LUAD. In vivo studies using nude mice with subcutaneously transplanted LUAD cells demonstrated that stable METTL14 knockdown led to notably reduced tumor volume and weight, along with fewer Ki67-positive cells and lung metastatic sites. Importantly, METTL14 knockdown reduced glycolytic activity in LUAD cells. Through a combination of RNA sequencing and MeRIP-sequencing, we identified numerous altered genes and confirmed that IGF2BP2 enhances G6PD mRNA stability after METTL14-mediated m6A modification, thereby promoting tumor growth and metastasis. Moreover, LUAD patients with higher levels of G6PD had poorer overall survival (OS). In conclusion, our study indicates that METTL14 upregulates G6PD expression post-transcriptionally through an m6A-IGF2BP2-dependent mechanism, thereby stabilizing G6PD mRNA. These findings propose potential diagnostic biomarkers and effective targets for anti-metabolism therapy in LUAD.

N6-methyladenosine-mediated LINC01087 promotes lung adenocarcinoma progression by regulating miR-514a-3p to upregulatecentrosome protein 55.

Long noncoding RNAs are key players in the development of lung adenocarcinoma (LUAD). The present study elucidated the role of LINC01087 in LUAD development. Cell vitality and apoptosis were assessed by the CCK-8 assay and flow cytometry, respectively. The transwell assay was adopted to evaluate cell migration and invasion. Levels of m6A modification of LINC01087 were determined using the methylated RNA binding protein immunoprecipitation assay. The interactions among LINC01087, miR-514a-3p, and centrosome protein 55 (CEP55) were evaluated using dual-luciferase reporter, RNA immunoprecipitation, and RNA-RNA pull-down assays. LINC01087 was highly expressed in LUAD, and its downregulation restrained cancer cell proliferation, migration, invasion, and epithelial-mesenchymal transition in vitro as well as tumor growth in a xenograft tumor model. Overexpression of miR-514a-3p inhibited malignant phenotypes in LUAD cells by inactivating RhoA/ROCK1 signaling via the suppression of CEP55 expression. Mechanistically, RBM15 increased the expression and mRNA stability of LINC01087 by mediating its m6A modification and LINC01087 induced CEP55 expression by sponging miR-514a-3p. RBM15-induced LINC01087 upregulation accelerated LUAD progression by regulating the miR-514a-3p/CEP55/RhoA/ROCK1 axis, illustrating the potential of LINC01087 as a novel target for LUAD therapy.

Aging-associated Alterations in the Gene Regulatory Network Landscape Associate with Risk, Prognosis and Response to Therapy in Lung Adenocarcinoma.

Aging is the primary risk factor for many individual cancer types, including lung adenocarcinoma (LUAD). To understand how aging-related alterations in the regulation of key cellular processes might affect LUAD risk and survival outcomes, we built individual (person)-specific gene regulatory networks integrating gene expression, transcription factor protein-protein interaction, and sequence motif data, using PANDA/LIONESS algorithms, for both non-cancerous lung tissue samples from the Genotype Tissue Expression (GTEx) project and LUAD samples from The Cancer Genome Atlas (TCGA). In GTEx, we found that pathways involved in cell proliferation and immune response are increasingly targeted by regulatory transcription factors with age; these aging-associated alterations are accelerated by tobacco smoking and resemble oncogenic shifts in the regulatory landscape observed in LUAD and suggests that dysregulation of aging pathways might be associated with an increased risk of LUAD. Comparing normal adjacent samples from individuals with LUAD with healthy lung tissue samples from those without LUAD, we found that aging-associated genes show greater aging-biased targeting patterns in younger individuals with LUAD compared to their healthy counterparts of similar age, a pattern suggestive of age acceleration. This implies that an accelerated aging process may be responsible for tumor incidence in younger individuals. Using drug repurposing tool CLUEreg, we found small molecule drugs with potential geroprotective effects that may alter the accelerating aging profiles we found. We also observed that, in contrast to chronological age, a network-informed aging signature was associated with survival and response to chemotherapy in LUAD.

A random forest model to predict the efficacy of anti-PD-1/PD-L1 monoclonal antibody in lung adenocarcinoma.

e20558 Background: Not all patients with lung adenocarcinoma (LUAD) could benefit from anti-PD-1/PD-L1 monoclonal antibody therapy, and existing biomarkers cannot explain all clinical benefits. Therefore, an effective model to predict the efficacy of anti-PD-1/PD-L1 monoclonal antibody is necessary. Methods: DNA methylation sequencing was used in LUAD patients’ FFPE samples, who received anti-PD-1/PD-L1 monoclonal antibody. The DNA methylation level of each gene was transformed into binary format according to its median value. The progression-free survival (PFS) was defined as the duration from the beginning of anti-PD-1/PD-L1 monoclonal antibody therapy to disease progression or death. Patients were randomly divided into training cohort (70%) and test cohort (30%). In the training cohort, uni-Cox regression was used to estimate the value in predicting PFS, and LASSO-Cox regression was performed to screened genes to build random forest model. The accuracy of this random forest model was validated in the test cohort. Finally, DNA methylation data were used to calculated the risk score of patients in the TCGA-LUAD cohort, and GSEA and GSVA were employed in RNA data to explore the mechanism and explain the efficacy of the prediction model. Results: In this study, 40 patients with LUAD were enrolled, and the median PFS of them was 7.57 months. A total of 29 genes with P &lt; 0.05 and C-index &gt; 0.7 were selected to perform LASSO-Cox regression, and 13 genes ( BTBD7, CAD, FBXL20, FKBP7, HBP1, IGFBP3, RAB5B, RASGRP1, RNF8, SOHLH1, TMEM223, UHRF1 and WWC2) were used to build prediction model. The C-index of risk score from this model was 0.96 and 0.93 in the training and test cohort, respectively. Patients were divided into the high and low risk groups according to the median risk score, and the median PFS of the high risk group was shorter than that of the low risk group (training cohort: 3.05 vs. 10.89 months, P &lt; 0.01, HR = 2.51, 95% CI: 1.50-4.22; test cohort: 1.64 vs. 11.31 months, P = 0.03, HR = 1.80, 95% CI: 1.04-3.14). In the low and high risk group of the TCGA-LUAD cohort, there were 92.2% (388/421) and 0.5% (2/421) significant enriched ( P &lt; 0.05 and FDR &lt; 0.25) immunity-related pathways from results of GSEA, respectively, meanwhile 94.3% (397/421) and 1.9% (8/421) significant enriched immunity-related pathways from results of GSVA, respectively. Therefore, the lower risk score of this random forest model accompanied with the higher activation of immunity-related pathways which might help anti-PD-1/PD-L1 monoclonal antibody to express better efficacy. Conclusions: A random forest model based on DNA methylation data was constructed and showed a potential value in predicting the PFS of anti-PD-1/PD-L1 monoclonal antibody therapy in LUADs, and the risk score of this model is negatively correlated to the activation of immunity-related pathways, which could help to identify LUAD patients that would benefit from immunotherapy.

A retrospective study of first-line therapy and subsequent pyrotinib treatment in advanced lung adenocarcinoma with HER2 mutations.

HER2 is an infrequently mutated driver gene in non-small cell lung cancer (NSCLC). At present, there has been no comprehensive large-scale clinical study to establish the optimal first-line treatment strategy for advanced lung adenocarcinoma (LUAD) with HER2-Mutant. Besides that, the effectiveness and safety of pyrotinib, a pan-HER inhibitor, in the context of NSCLC are still undergoing investigation. In this study, we conducted a retrospective data collection of HER2-Mutated advanced LUAD who received first-line treatment and pyrotinib between May 2014 and June 2023. Patients treated with chemotherapy, chemotherapy + immune checkpoint inhibitors (ICIs), chemotherapy + bevacizumab and pyrotinib in first-line treatment. Furthermore, we collected data on the efficacy and safety of pyrotinib in these patients after disease progression. The main endpoint of the study was progression-free survival (PFS). In the final analysis, 89 patients were included in the first-line cohort and 30 patients were included in the pyrotinib cohort. In the first-line treatment cohort, chemotherapy + ICIs, chemotherapy + bevacizumab, and pyrotinib exhibited notable survival benefits compared to chemotherapy (median PFS: 9.87 vs. 7.77 vs. 7.10 vs. 5.40 months, p-value < 0.05). Furthermore, patients with a first-line treatment PFS of less than 6 months may potentially benefit from subsequent treatment with pyrotinib (median PFS: 7.467 vs. 3.000, p-value = 0.0490). In the first-line treatment of HER2-Mutant LUAD, regimens involving combinations like chemotherapy + ICIs, chemotherapy + bevacizumab, and pyrotinib may confer enhanced survival advantages compared to chemotherapy. Nevertheless, no significant distinctions were observed among these three treatment strategies, underscoring the imperative to identify biomarkers for the discerning selection of suitable therapeutic modalities. Moreover, patients with suboptimal response to first-line treatment may potentially derive more benefit from pyrotinib.

PD-(L)1 inhibitors plus bevacizumab and chemotherapy as first-line therapy in PD-L1 negative metastatic lung adenocarcinoma: A real-world data.

e20577 Background: Chemotherapies combined with immune checkpoint inhibitors (ICIs) and/or bevacizumab (named IC, BC and IBC respectively) are the preferred first-line options for PD-L1 negative and oncogenic driver wild-type metastatic lung adenocarcinoma. However, the optimal strategy is still undetermined. Methods: This retrospective real-world study enrolled PD-L1 negative metastatic lung adenocarcinoma patients from four cancer centers between January 1, 2018 and June 30, 2022. All the patients received IC, BC, or IBC as the first-line therapies. The efficacy and safety were evaluated. Results: A total of 205 patients were included, with 60, 83, and 62 patients in IC, BC, and IBC groups, respectively. Patients receiving IBC obtained the highest objective response rate (ORR) (43.5%) and disease control rate (DCR) (100%) relative to those receiving IC (40.4%, 84.2%) or BC (40.5%, 96.2%). Compared with the IC (6.74m) or BC (8.28m) group, IBC group improved significantly median progression-free survival (mPFS) (9.53m, P = 0.005). However, the difference in overall survival (OS) were not observed among the three groups. When analyzed based on different clinical and molecular information, we found that male gender, ever smoking, wild-type genes, and adrenal metastasis predicts superior PFS benefit when treated with IBC. In patients with liver metastasis, IBC or BC treatment achieved better PFS compared with IC. No additional adverse reactions were observed in IBC group compared with other two groups. Conclusions: Combined IBC treatment achieved superior DCR and PFS compared with IC or BC treatment in patients with PD-L1 negative metastatic lung adenocarcinoma, while did not increase the adverse events.

Response to first-line therapies in metastatic lung adenocarcinoma with low PD-L1 expression: A multi-center retrospective study.

e20574 Background: For metastatic lung adenocarcinoma with low PD-L1 expression (tumor proportion score:1-49%), chemotherapy in combination with immune checkpoint inhibitors (IC), with bevacizumab (BC), or with both (IBC) have been established as standard first-line options. However, the optimal scheme is still undetermined. Methods: This retrospective study enrolled 125 metastatic lung adenocarcinoma patients with low PD-L1 expression from four cancer centers. All the patients received IC, BC, or IBC as the first-line therapies. Propensity score matching (PSM) with a ratio of 1:1:1 was used to balance the inter-group clinical characteristics. Efficacy, including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS), as well as safety were evaluated. Results: 35 of the 125 patients received IBC, 37 received BC, and 53 received IC. After PSM, a total of 35 pairs of patients were enrolled in the analysis. Patients receiving IBC (ORR: 57.1%, DCR:100%) or IC (ORR: 57.1%, DCR: 91.4%) obtained superior ORR and DCR in relative to those receiving BC (ORR: 45.7%, DCR: 82.9%). However, only IBC (median PFS: 20.47m; median OS: not research) rather than IC (median PFS: 10.0m; median OS: 21.36m) treatment generated significantly prolonged PFS and OS compared with BC (median PFS: 9.43m, P = 0.007; median OS: 23.2m, P = 0.048). We further analyzed the survival benefit based on different clinical and molecular features. We found patients with female gender had more significant OS benefit from IBC treatment over IC or BC treatment. In addition, non-smokers benefit more from IBC compared with IC. The occurrence of adverse events (AEs) was more frequent in IBC (74.3%) and IC (85.7%) group in relative to BC group (42.8%). Meanwhile, ≥ grade 3 AEs (22.9%) was markedly higher in IBC group compared with that in BC group (5.7%). However, leukopenia and neutropenia represent the most common ≥ grade 3 AEs, which are easy to be clinically managed. Conclusions: For metastatic lung adenocarcinoma patients with low PD-L1 expression, IBC is the preferred first-line therapy in terms of survival. However, the AEs should be carefully concerned.

High TLX1 Expression Correlates with Poor Prognosis and Immune Infiltrates in Patients with Lung Adenocarcinoma.

To develop optimal personalized therapy for lung adenocarcinoma (LUAD), potential biomarkers associated with the prognosis are urgently needed. It is unclear what role T Cell Leukemia Homeobox 1 (TLX1) plays in LUAD. In this study, TLX1's relationship with LUAD was investigated using TCGA database analysis, bioinformatics analysis, and experimental validation. We examined the expression of TLX1 in pan cancer and LUAD, the relationship between TLX1 expression and clinical features, immune infiltration, its diagnostic and prognostic value, as well as TLX1 related pathways. The analysis included various statistical methods, including the Kaplan-Meier method, Cox regression analysis, GSEA, and immune infiltration analysis. TLX1 expression in LUAD cell lines was validated using qRT-PCR. In LUAD patients, high expression of TLX1 was associated with T stage (P<0.001). High TLX1 expression was associated with worse overall survival (OS) (HR: 1.57; 95% CI: 1.18-2.1; P=0.002). And TLX1 HR: 1.619; 95% CI: 1.012-2.590; P=0.044) was independently correlated with OS in LUAD patients. TLX1 expression was associated with the pathways, including Rho GTPase effectors, DNA repair, TCF dependent signaling in response to WNT, signaling by Nuclear Receptors, signaling by Notch, chromatin-modifying enzymes, ESR-mediated signaling, cellular senescence, and transcriptional regulation by Runx1. TLX1 expression was correlated with aDC, Tcm, and TReg cells. The expression of TLX1 was significantly increased in LUAD cells compared to BEAS-2B cells. An association between high TLX1 expression and poor survival and immune infiltration was found in LUAD patients. There may be a potential role for TLX1 in diagnosis, prognosis, and immunotherapy for LUAD.

Chaperonin-containing TCP-1 subunit genes are potential prognostic biomarkers and are correlated with Th2 cell infiltration in lung adenocarcinoma: An observational study.

A family of molecular chaperone complexes called chaperonin-containing T-complex protein 1 (TCP-1) subunit genes (CCTs) aids in the folding of numerous proteins. With regard to lung adenocarcinoma (LUAD), this study provided a thorough understanding of the diagnostic and prognostic use of CCTs. The expression of CCTs in LUAD was evaluated by using databases including UALCAN and the Gene Expression Omnibus. Immunohistochemistry (IHC) was conducted to validate the expression of CCTs in LUAD. The mutation in the CCTs was identified through the cBioPortal database, while promoter methylation was measured by the UALCAN database. The prognostic value of CCTs was evaluated using the PrognoScan analysis. The GEPIA2.0 database was used to measure the prognostic value of CCTs and associated Hub genes. Correlation analysis between CCTs expression in LUAD was based on the GEPIA2.0 database. The ROC curves, clinical correlation analysis, gene ontology, Kyoto Encyclopedia of Genes and Genome analysis, and immune cell infiltration analysis were downloaded from The Cancer Genome Atlas database and then analyzed and visualized using the R language. The STRING database was used for protein-protein interaction analysis. Upregulation of CCTs expression in patients with LUAD indicated advanced diseases and a poor prognosis. ROC curve analysis revealed that the CCTs may serve as diagnostic indicators. The functional enrichment analysis showed that CCTs were involved in the mitosis-mediated cell cycle process. Additionally, 10 hub genes associated with CCTs that were linked to LUAD prognosis and tumor progression were identified. Immune cell infiltration analysis showed that CCTs expression in tumor tissues tends to be related to T helper type 2 cell infiltration. This study revealed that CCTs may serve as valuable biomarkers for the diagnosis and targeted therapy of LUAD.

Somatic KMT2D loss-of-function mutations in lung squamous cell carcinoma: a single-center cohort study.

The significant progress has been made in targeted therapy for lung adenocarcinoma (LUAD) in the past decade. Only few targeted therapeutics have yet been approved for the treatment of lung squamous cell carcinoma (LUSC). Several higher frequency of gene alterations are identified as potentially actionable in LUSC. Our work aimed to explore the complex interplay of multiple genetic alterations and pathways contributing to the pathogenesis of LUSC, with a very low frequency of a single driver molecular alterations to develop more effective therapeutic strategies in the future. We retrospectively analyzed the targeted next-generation sequencing (NGS) data (approximately 600 genes) of 335 patients initially diagnosed with non-small cell lung cancer (NSCLC) at our institution between January 2019 and March 2023 and explored the somatic genome alteration difference between LUSC and LUAD. We analyzed that the presence of loss-of-function (LoF) mutations (nonsense, frameshift, and splice-site variants) in histone-lysine N-methyltransferase 2D (KMT2D) was much more prevalent in LUSC (11/53, 20.8%) than in LUAD (6/282, 2.1%). Moreover, our data indicated TP53 co-mutated with KMT2D LoF in 90.9% (10/11) LUSC and 33.3% (2/6) LUAD. Notably, the mutation allele fraction (MAF) of KMT2D was very similar to that of TP53 in the co-mutated cases. Genomic profiling of driver gene mutations of NSCLC showed that 81.8% (9/11) of the patients with LUSC with KMT2D LoF mutations had PIK3CA amplification and/or FGFR1 amplification. Our results prompted that somatic LoF mutations of KMT2D occur frequently in LUSC, but are less frequent in LUAD and therefore may potentially contribute to the pathogenesis of LUSC. Concurrent TP53 mutations, FGFR1 amplification, and PIK3CA amplification are very common in LUSC cases with KMT2D LoF mutations. It needs more deeper investigation on the interplay of the genes and pathways and uses larger cohorts in the future.

PCDH11X mutation as a potential biomarker for immune checkpoint therapies in lung adenocarcinoma.

Immune checkpoint inhibitors (ICIs) have achieved impressive success in lung adenocarcinoma (LUAD). However, the response to ICIs varies among patients, and predictive biomarkers are urgently needed. PCDH11X is frequently mutated in LUAD, while its role in ICI treatment is unclear. In this study, we curated genomic and clinical data of 151 LUAD patients receiving ICIs from three independent cohorts. Relations between PCDH11X and treatment outcomes of ICIs were examined. A melanoma cohort collected from five published studies, a pan-cancer cohort, and non-ICI-treated TCGA-LUAD cohort were also examined to investigate whether PCDH11X mutation is a specific predictive biomarker for LUAD ICI treatment. Among the three ICI-treated LUAD cohorts, PCDH11X mutation (PCDH11X-MUT) was associated with better clinical response compared to wild-type PCDH11X (PCDH11X-WT). While in ICI-treated melanoma cohort, the pan-cancer cohort excluding LUAD, and the non-ICI-treated TCGA-LUAD cohort, no significant differences in overall survival (OS) were observed between the PCDH11X-MUT and PCDH11X-WT groups. PCDH11X mutation was associated with increased PD-L1 expression, tumor mutation burden (TMB), neoantigen load, DNA damage repair (DDR) mutations, and hot tumor microenvironment in TCGA-LUAD cohort. Our findings suggested that the PCDH11X mutation might serve as a specific biomarker to predict the efficacy of ICIs for LUAD patients. Considering the relatively small sample size of ICI-treated cohorts, future research with larger cohorts and prospective clinical trials will be essential for validating and further exploring the role of PCDH11X mutation in the context of immunotherapy outcomes in LUAD. KEY MESSAGES: PCDH11X mutation is associated with better clinical response compared to wild type PCDH11X in three ICIs-treated LUAD cohorts. In ICIs-treated melanoma cohort, the pan-cancer cohort excluding LUAD, and non-ICIs-treated TCGA-LUAD cohortsPCDH11X mutation is not associated with better clinical response, suggesting PCDH11X mutation might be a specific biomarker to predict the efficacy of ICIs treatment for LUAD patients. PCDH11X mutation is associated with increased PD-L1 expression, tumor mutation burden, and neoantigen load in TCGA-LUAD cohort. PCDH11X mutation is associated with hot tumor microenvironment in TCGA-LUAD cohort.

An original aneuploidy-related gene model for predicting lung adenocarcinoma survival and guiding therapy.

Aneuploidy is a hallmark of cancers, but the role of aneuploidy-related genes in lung adenocarcinoma (LUAD) and their prognostic value remain elusive. Gene expression and copy number variation (CNV) data were enrolled from TCGA and GEO database. Consistency clustering analysis was performed for molecular cluster. Tumor microenvironment was assessed by the xCell and ESTIMATE algorithm. Limma package was used for selecting differentially expressed genes (DEGs). LASSO and stepwise multivariate Cox regression analysis were used to establish an aneuploidy-related riskscore (ARS) signature. GDSC database was conducted to predict drug sensitivity. A nomogram was designed by rms R package. TCGA-LUAD patients were stratified into 3 clusters based on CNV data. The C1 cluster displayed the optimal survival advantage and highest inflammatory infiltration. Based on integrated intersecting DEGs, we constructed a 6-gene ARS model, which showed effective prediction for patient's survival. Drug sensitivity test predicted possible sensitive drugs in two risk groups. Additionally, the nomogram exhibited great predictive clinical treatment benefits. We established a 6-gene aneuploidy-related signature that could effectively predict the survival and therapy for LUAD patients. Additionally, the ARS model and nomogram could offer guidance for the preoperative estimation and postoperative therapy of LUAD.

Integrated analysis highlights the significance role of ITGAL in lung adenocarcinoma.

Integrin alpha L (ITGAL), a member of the integrin family, is associated with carcinogenesis and immune regulation. However, the biological functions of ITGAL in lung adenocarcinoma (LUAD) remain poorly understood. In this study, we utilized the TCGA dataset to analyse ITGAL mRNA expression in LUAD and examined its correlation with clinical prognosis. Three-dimensional (3D) Matrigel culture, 5-bromodeoxyuridine (BrdU) ELISA, wound-healing migration and cell adherence assays were used to demonstrate the potential role of ITGAL in LUAD progression. Additionally, we analysed single-cell sequencing data of LUAD to determine the expression and biological function of ITGAL. Our research revealed that the expression of ITGAL in LUAD samples is an independent predictor of prognosis. Patients with high expression of ITGAL had significantly better overall survival (OS), progression-free survival (PFS) and disease-specific survival (DSS) compared to the low-expression group. Meanwhile, the expression of ITGAL suppressed malignant progression in LUAD cells. Functional enrichment analyses showed that ITGAL was significantly correlated with cell immune response and immune checkpoint, consistent with the analysis of single-cell sequencing in paired samples of normal and tumour. Furthermore, we confirmed that ITGAL expression affect the tumour microenvironment (TME) through regulation of the expression of cytokines in NK cells of LUAD. In summary, ITGAL is a prognostic biomarker for LUAD patients, and it repressed malignant progression in LUAD cells. Moreover, ITGAL expression also enhanced the effect of immunotherapy and may be an important target in LUAD therapy.

DEPDC1 is a potential therapeutic target in lung adenocarcinoma

Lung cancer, as a highly malignant neoplasm, leads to elevated morbidity and mortality rates owing to the absence of reliable approaches for prompt diagnosis and intervention. It is crucial to investigate the mechanisms underlying lung cancer development and identify biomarkers to achieve early detection and treatment. In this study, DEP domain containing 1 (DEPDC1), was identified as a hub gene with higher expression in lung adenocarcinoma (LUAD) through weighted gene co-expression network and protein-protein interaction analyses. Patients with high DEPDC1 expression had worse survival rates, and gene set enrichment analysis revealed that DEPDC1 may participate in oncogenic progression via NF-κB-mediated signaling pathways, including the cell cycle and epithelial-mesenchymal transition. DEPDC1 knockdown significantly inhibited cancer cell proliferation and motility. Further, we demonstrated that an ionizable lipid nanoparticle delivering DEPDC1 small interfering RNA effectively inhibited tumor growth in vivo, with few systemic adverse effects. Collectively, our current investigation illustrates that DEPDC1 is a potential target for LUAD therapy.

Clinical outcome of bevacizumab or ramucirumab combined with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors as the first line therapy in susceptible EGFR-mutated advanced non-small-cell lung.

Combining epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with an anti- vascular endothelial growth factor (VEGF) agent, bevacizumab or ramucirumab, is indicated for advanced lung adenocarcinoma harboring EGFR mutation. This study aimed to show the real-world data of combination therapy and compare the effectiveness between bevacizumab and ramucirumab in combination with an EGFR-TKI. This retrospective study enrolled 47 patients diagnosed of stage IV lung adenocarcinoma with exon 19 deletion or L858R point mutation, receiving a first-line EGFR-TKI with anti-VEGF agent, including 34 (72%) and 13 (28%) patients receiving bevacizumab and ramucirumab, respectively. The response rate was similar in both groups (p = 0.38). Patients receiving bevacizumab had similar progression free survival (PFS) as those receiving ramucirumab (median PFS: 21.9 vs. 24.2 months, p = 0.4871); similar finding was noted in overall survival (OS) (median OS: 33.5 months vs. not reached, p = 0.4618). Patients receiving ramucirumab experienced a significantly high-grade hypertension compared to those receiving bevacizumab (p = 0.0351). Multivariable Cox regression analysis found independent risk factors for worse PFS included poorer ECOG performance status, multiple (≥3) metastatic sites, brain metastasis, and pleural metastasis/effusion, while the type of anti-VEGF agent was not a risk factor. Pericardial metastasis/effusion was the only one independent risk factor for worse OS. In summary, ramucirumab may have similar effectiveness as bevacizumab in combination with an EGFR-TKI as first line therapy for advanced lung adenocarcinoma harboring susceptible EGFR mutation. Further large-scale registry-based cohort studies may be needed to validate our findings.