bims-meluca 2024-06-30 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2024–06–30
seven papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Can blood-based markers predict RECIST progression in non-small cell lung cancer treated with immunotherapy?
Plasmatic Inactive IL-18 Predicts a Worse Overall Survival for Advanced Non-Small-Cell Lung Cancer with Early Metabolic Progression after Immunotherapy Initiation.
Identification of subgroups and development of prognostic risk models along the glycolysis-cholesterol synthesis axis in lung adenocarcinoma.
Circulating receptor activator of nuclear factor kappa-B ligand (RANKL) levels predict response to immune checkpoint inhibitors in advanced non-small cell lung cancer (NSCLC).
The Nucleolar Protein C1orf131 Is a Novel Gene Involved in the Progression of Lung Adenocarcinoma Cells through the AKT Signalling Pathway.
Downregulated CDK10 promotes cancer progression and radioresistance in lung cancer through activating the JNK/c-Jun signaling pathway.
Identification of lung adenocarcinoma subtypes based on mitochondrial energy metabolism-related genes.

J Cancer Res Clin Oncol. 2024 Jun 26. 150(6): 329

Can blood-based markers predict RECIST progression in non-small cell lung cancer treated with immunotherapy?

Melda Yeghaian, Teresa M Tareco Bucho, Melissa de Bruin, Alexander Schmitz, Zuhir Bodalal, Egbert F Smit, Regina G H Beets-Tan, Daan van den Broek, Stefano Trebeschi.

   PURPOSE: In this study, we aimed to evaluate the potential of routine blood markers, serum tumour markers and their combination in predicting RECIST-defined progression in patients with stage IV non-small cell lung cancer (NSCLC) undergoing treatment with immune checkpoint inhibitors.
METHODS: We employed time-varying statistical models and machine learning classifiers in a Monte Carlo cross-validation approach to investigate the association between RECIST-defined progression and blood markers, serum tumour markers and their combination, in a retrospective cohort of 164 patients with NSCLC.
RESULTS: The performance of the routine blood markers in the prediction of progression free survival was moderate. Serum tumour markers and their combination with routine blood markers generally improved performance compared to routine blood markers alone. Elevated levels of C-reactive protein (CRP) and alkaline phosphatase (ALP) ranked as the top predictive routine blood markers, and CYFRA 21.1 was consistently among the most predictive serum tumour markers. Using these classifiers to predict overall survival yielded moderate to high performance, even when cases of death-defined progression were excluded. Performance varied across the treatment journey.
CONCLUSION: Routine blood tests, especially when combined with serum tumour markers, show moderate predictive value of RECIST-defined progression in NSCLC patients receiving immune checkpoint inhibitors. The relationship between overall survival and RECIST-defined progression may be influenced by confounding factors.

Keywords:   NSCLC; Blood-based markers; Immunotherapy; Machine learning; Progression-free survival; RECIST

DOI:  https://doi.org/10.1007/s00432-024-05814-2
Cancers (Basel). 2024 Jun 14. pii: 2226. [Epub ahead of print]16(12):

Plasmatic Inactive IL-18 Predicts a Worse Overall Survival for Advanced Non-Small-Cell Lung Cancer with Early Metabolic Progression after Immunotherapy Initiation.

Serena Janho Dit Hreich, Olivier Humbert, Tanguy Pacé-Loscos, Renaud Schiappa, Thierry Juhel, Marius Ilié, Victoria Ferrari, Jonathan Benzaquen, Paul Hofman, Valérie Vouret-Craviari.

  The aim of this study was to assess the potential value of circulating active and inactive IL-18 levels in distinguishing pseudo and true tumor progression among NSCLC patients receiving immune checkpoint inhibitor treatments (ICIs).
METHODS: This ancillary study includes 195 patients with metastatic non-small-cell lung cancer (NSCLC) treated with ICI in monotherapy, either pembrolizumab or nivolumab. Plasmatic levels of IL-18-related compounds, comprising the inhibitor IL-18 binding protein (IL-18BP), the inactive IL-18 (corresponding to IL-18/IL-18BP complex), and the active free IL-18, were assayed by ELISA. Objective tumoral response was analyzed by 18FDG PET-CT at baseline, 7 weeks, and 3 months post treatment induction, using PERCIST criteria.
RESULTS: Plasmatic IL-18BP and total IL-18 levels are increased at baseline in NSCLC patients compared with healthy controls, whereas IL-18/IL-18BP complexes are decreased, and free IL-18 levels remain unchanged. Neither of the IL-18-related compounds allowed to discriminate ICI responding to nonresponding patients. However, inactive IL-18 levels allowed to discriminate patients with a first tumor progression, assessed after 7 weeks of treatment, with worse overall survival. In addition, we showed that neutrophil concentration is also a predictive indicator of patients' outcomes with OS (HR = 2.6, p = 0.0001) and PFS (HR = 2.2, p = 0.001).
CONCLUSIONS: Plasmatic levels of inactive IL-18, combined with circulating neutrophil concentrations, can effectively distinguish ICI nonresponding patients with better overall survival (OS), potentially guiding rapid decisions for therapeutic intensification.

Keywords:  IL-18 signaling pathways; immune checkpoint inhibitor; lung adenocarcinoma; neutrophils

DOI:  https://doi.org/10.3390/cancers16122226
Sci Rep. 2024 06 26. 14(1): 14704

Identification of subgroups and development of prognostic risk models along the glycolysis-cholesterol synthesis axis in lung adenocarcinoma.

Jiuzhou Jiang, Bao Qian, Yangjie Guo, Zhengfu He.

  Lung cancer is one of the most dangerous malignant tumors affecting human health. Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer. Both glycolytic and cholesterogenic pathways play critical roles in metabolic adaptation to cancer. A dataset of 585 LUAD samples was downloaded from The Cancer Genome Atlas database. We obtained co-expressed glycolysis and cholesterogenesis genes by selecting and clustering genes from Molecular Signatures Database v7.5. We compared the prognosis of different subtypes and identified differentially expressed genes between subtypes. Predictive outcome events were modeled using machine learning, and the top 9 most important prognostic genes were selected by Shapley additive explanation analysis. A risk score model was built based on multivariate Cox analysis. LUAD patients were categorized into four metabolic subgroups: cholesterogenic, glycolytic, quiescent, and mixed. The worst prognosis was the mixed subtype. The prognostic model had great predictive performance in the test set. Patients with LUAD were effectively typed by glycolytic and cholesterogenic genes and were identified as having the worst prognosis in the glycolytic and cholesterogenic enriched gene groups. The prognostic model can provide an essential basis for clinicians to predict clinical outcomes for patients. The model was robust on the training and test datasets and had a great predictive performance.

Keywords:  Cholesterol; Glycolysis; SHAP; XGBoost

DOI:  https://doi.org/10.1038/s41598-024-64602-7
J Immunother Cancer. 2024 Jun 21. pii: e009432. [Epub ahead of print]12(6):

Circulating receptor activator of nuclear factor kappa-B ligand (RANKL) levels predict response to immune checkpoint inhibitors in advanced non-small cell lung cancer (NSCLC).

Michele Iuliani, Sonia Simonetti, Leonardo Cristofani, Silvia Cavaliere, Alessio Cortellini, Marco Russano, Bruno Vincenzi, Giuseppe Tonini, Daniele Santini, Francesco Pantano.

   BACKGROUND: Receptor activator of nuclear factor kappa-B ligand (RANKL) can directly promote tumor growth and indirectly support tumor immune evasion by altering the tumor microenvironment and immune cell responses. This study aimed to assess the prognostic significance of soluble RANKL in patients with advanced non-small cell lung cancer (NSCLC) receiving programmed cell death 1 (PD1)/programmed death-ligand 1 (PDL1) checkpoint inhibitor therapy.
METHODS: Plasma RANKL levels were measured in 100 patients with advanced NSCLC without bone metastases undergoing monotherapy with PD1/PDL1 checkpoint inhibitors. To establish the optimal cut-off value, we used the Cutoff Finder package in R. Survival curves for four distinct patient groups, according to their RANKL and PDL1 levels (high or low), were generated using the Kaplan-Meier method and compared with the log-rank test. The Cox regression model calculated HRs and 95% CIs for overall survival (OS) and progression-free survival (PFS).
RESULTS: The optimal RANKL cut-off was established at 280.4 pg/mL, categorizing patients into groups with high or low RANKL levels. A significant association was observed between increased RANKL concentrations and decreased survival rates at 24 months, only within the subgroup expressing high levels of PDL1 (p=0.002). Additionally, low RANKL levels in conjunction with elevated PDL1 expression correlated with improved PFS (median 22 months, 95% CI 6.70 to 50 vs median 4 months, 95% CI 3.0 to 7.30, p=0.009) and OS (median 26 months, 95% CI 20 to not reached vs median 7 months, 95% CI 6 to 13, p=0.003), indicating RANKL's potential as an indicator of adverse prognosis in these patients. Multivariate analysis identified RANKL as an independent negative prognostic factor for both PFS and OS, regardless of other clinicopathological features.
CONCLUSION: These results highlight the prognostic and predictive value of RANKL specifically in patients with high PDL1 expression.

Keywords:  Immune Checkpoint Inhibitor; Lung Cancer

DOI:  https://doi.org/10.1136/jitc-2024-009432
Int J Mol Sci. 2024 Jun 09. pii: 6381. [Epub ahead of print]25(12):

The Nucleolar Protein C1orf131 Is a Novel Gene Involved in the Progression of Lung Adenocarcinoma Cells through the AKT Signalling Pathway.

Zhili Wei, Yiming Zhao, Jing Cai, Yajun Xie.

  Lung adenocarcinoma (LUAD) is the most widespread cancer in the world, and its development is associated with complex biological mechanisms that are poorly understood. Here, we revealed a marked upregulation in the mRNA level of C1orf131 in LUAD samples compared to non-tumor tissue samples in The Cancer Genome Atlas (TCGA). Depletion of C1orf131 suppressed cell proliferation and growth, whereas it stimulated apoptosis in LUAD cells. Mechanistic investigations revealed that C1orf131 knockdown induced cell cycle dysregulation via the AKT and p53/p21 signalling pathways. Additionally, C1orf131 knockdown blocked cell migration through the modulation of epithelial-mesenchymal transition (EMT) in lung adenocarcinoma. Notably, we identified the C1orf131 protein nucleolar localization sequence, which included amino acid residues 137-142 (KKRKLT) and 240-245 (KKKRKG). Collectively, C1orf131 has potential as a novel therapeutic marker for patients in the future, as it plays a vital role in the progression of lung adenocarcinoma.

Keywords:  C1orf131; cell cycle; lung cancer; nucleolar protein; proliferation

DOI:  https://doi.org/10.3390/ijms25126381
BMB Rep. 2024 Jun 26. pii: 6209. [Epub ahead of print]

Downregulated CDK10 promotes cancer progression and radioresistance in lung cancer through activating the JNK/c-Jun signaling pathway.

Chaojin Hong, Yimei Meng, Anchen Qiu, Haibo Zhang, Liu Yang, Yupeng Hong, Yumei Huang.

Lung cancer is one of the most significant malignancies, with both high morbidity and mortality. CDK10 is closely related to cancer progression and metastasis. However, its role in lung cancer radioresistance demands further clarification. In this study, we demonstrated that CDK10 was downregulated in lung cancer tissues, and CDK10 expression level was associated with the clinical prognosis in lung cancer patients. We also found that silencing CDK10 promoted lung cancer cell proliferation, migration, and radioresistance. We further verified that silencing CDK10 facilitated the activation of JNK/c-Jun signaling, and c-Jun depletion could reverse the effects of CDK10 knockdown in lung cancer cells. Our findings revealed that CDK10 plays an important role in cell growth and radioresistance by inhibiting JNK/c-Jun signaling pathway in lung cancer. Therefore, CDK10 might be a promising therapeutic target in lung cancer.
Nucleosides Nucleotides Nucleic Acids. 2024 Jun 26. 1-19

Identification of lung adenocarcinoma subtypes based on mitochondrial energy metabolism-related genes.

Jianyang Ding, Keng Chen, Xuhui Wu.

   BACKGROUND: Identifying subtypes of lung adenocarcinoma (LUAD) patients based on mitochondrial energy metabolism and immunotherapy sensitivity is essential for precision cancer treatment.
METHODS: LUAD subtypes were identified using unsupervised consensus clustering, and results were subjected to immune and tumor mutation analyses. DEGs between subtypes were identified by differential analysis. Functional enrichment and PPI network analyses were conducted. Patients were classified into high and low expression groups based on the expression of the top 10 hub genes, and survival analysis was performed. Drugs sensitive to feature genes were screened based on the correlation between hub gene expression and drug IC50 value. qRT-PCR and western blot were used for gene expression detection, and CCK-8 and flow cytometry were for cell viability and apoptosis analysis.
RESULTS: Cluster-1 had significantly higher overall survival and a higher degree of immunoinfiltration and immunophenotypic score, but a lower TIDE score, DEPTH score, and TMB. Enrichment analysis showed that pathways and functions of DEGs between two clusters were mainly related to the interaction of receptor ligands with intracellular proteases. High expression of hub genes corresponded to lower patient survival rates. The predicted drugs with high sensitivity to feature genes were CDK1: Ribavirin (0.476), CCNB2: Hydroxyurea (0.474), Chelerythrine (0.470), and KIF11: Ribavirin (0.471). KIF11 and CCNB2 were highly expressed in LUAD cells and promoted cell viability and inhibited cell apoptosis.
CONCLUSION: This study identified two subtypes of LUAD, with cluster-1 being more suitable for immunotherapy. These results provided a reference for the development of precision immunotherapy for LUAD patients.

Keywords:  Lung adenocarcinoma; drugs; immunotherapy; mitochondrial energy metabolism; prognosis

DOI:  https://doi.org/10.1080/15257770.2024.2369093