bims-meluca 2023-07-23 papers

Aging (Albany NY). 2023 Jul 20. 15

Characterization of platelet-related genes and constructing signature combined with immune-related genes for predicting outcomes and immunotherapy response in lung squamous cell carcinoma.

Siyi Zhao, Han Gong, Wenhua Liang.

Lung squamous cell carcinoma (LUSC) is a highly malignant subtype of non-small cell lung cancer with poor prognosis. Platelets are known to play a critical role in cancer development and progression, and recent studies suggest that they can also regulate immune response in tumors. However, the relationship between platelet-related genes (PRGs) and LUSC prognosis and tumor microenvironments remains unclear. In this study, we used multiple bioinformatics algorithms to identify 25 dysregulated PRGs that were significantly associated with LUSC prognosis. We found that PRGs were involved in multiple biological processes, particularly in the tumor microenvironment, and that platelet-related scores (PRS) were a risk factor. Additionally, we established a 6-gene prognostic signature combining PRGs and immune-related genes that accurately predicted outcomes and immunotherapy efficacy in LUSC patients. Our study provides a comprehensive analysis of the biological functions and potential therapeutic targets of PRGs in LUSC, which may inform the development of new treatments for this disease.

Keywords: immunity; lung squamous cell carcinoma; platelet-related genes; prognosis; tumor microenvironments

DOI: https://doi.org/10.18632/aging.204886

Lung Cancer. 2023 Jul 16. pii: S0169-5002(23)00846-2. [Epub ahead of print]183 107308

Gene-network analysis predicts clinical response to immunotherapy in patients affected by NSCLC.

Federico Cucchiara, Stefania Crucitta, Iacopo Petrini, Diego de Miguel Perez, Martina Ruglioni, Eleonora Pardini, Christian Rolfo, Romano Danesi, Marzia Del Re.

OBJECTIVES: Predictive biomarkers of response to immune checkpoint inhibitors (ICIs) have been extensively studied in non-small cell lung cancer (NSCLC) with controversial results. Recently, gene-network analysis emerged as a new tool to address tumor biology and behavior, representing a potential tool to evaluate response to therapies.
METHODS: Clinical data and genetic profiles of 644 advanced NSCLCs were retrieved from cBioPortal and the Cancer Genome Atlas (TCGA); 243 ICI-treated NSCLCs were used to identify an immunotherapy response signatures via mutated gene network analysis and K-means unsupervised clustering. Signatures predictive values were tested in an external dataset of 242 cases and assessed versus a control group of 159 NSCLCs treated with standard chemotherapy.
RESULTS: At least two mutations in the coding sequence of genes belonging to the chromatin remodelling pathway (A signature), and/or at least two mutations of genes involved in cell-to-cell signalling pathways (B signature), showed positive prediction in ICI-treated advanced NSCLC. Signatures performed best when combined for patients undergoing first-line immunotherapy, and for those receiving combined ICIs.
CONCLUSIONS: Alterations in genes related to chromatin remodelling complexes and cell-to-cell crosstalk may force dysfunctional immune evasion, explaining susceptibility to immunotherapy. Therefore, exploring mutated gene networks could be valuable for determining essential biological interactions, contributing to treatment personalization.

Keywords: Biomarkers; Co-occurring mutations; Gene network analysis; Immunotherapy; NSCLC

DOI: https://doi.org/10.1016/j.lungcan.2023.107308

J Thorac Oncol. 2023 Jul 18. pii: S1556-0864(23)00684-6. [Epub ahead of print]

KEAP1/NFE2L2 pathway signature outperforms KEAP1/NFE2L2 mutation status and reveals alternative pathway-activating mutations in Non-Small Cell Lung Cancer.

C Arolt, M Dugan, R Wild, V Richartz, B Holz, A H Scheel, J Bragelmann, S Wagener-Ryczek, S Merkelbach-Bruse, J Wolf, R Buettner, L Catanzariti, M Scheffler, A M Hillmer.

BACKGROUND: Activation of the antioxidant KEAP1/NFE2L2(NRF2)-pathway leads to increased glutamine dependence and an aggressive phenotype in non-small cell lung cancer (NSCLC). Since this pathway has been explored as a clinical target, we developed a transcriptomic signature for identifying KEAP1/NFE2L2-activated tumors.
MATERIAL AND METHODS: A total of 971 NSCLC were used to train an expression signature (K1N2-score) to predict KEAP1/NFE2L2 mutations. 348 in-house NSCLC were analyzed using a NanoString expression panel for validation.
RESULTS: The 46-gene K1N2-score robustly predicted KEAP1/NFE2L2 mutations in the validation set irrespective of histology and mutation (AUC:89.5, sensitivity:90.2%), suggesting that ∼90% of KEAP1/NFE2L2-mutations are pathway-activating. The K1N2-score outperformed KEAP1/NFE2L2 mutational status when predicting patient survival (score p=0.047; mutation p=0.215). In K1N2-score-positive, but KEAP1/NFE2L2wt samples, enrichment testing identified SMARCA4/BRG1 and CUL3 mutations as mimics of KEAP1/NFE2L2 mutations.
CONCLUSIONS: The K1N2-score identified KEAP1/NFE2L2-activated NSCLC by robustly detecting KEAP1/NFE2L2mut cases and discovering alternative genomic activators. It is a potential means for selecting patients with a constitutively active KEAP1/NFE2L2 pathway.

Keywords: KEAP1; NRF2; NSCLC; lung cancer; transcriptomics

DOI: https://doi.org/10.1016/j.jtho.2023.07.016

Nutrition. 2023 Jun 04. pii: S0899-9007(23)00143-0. [Epub ahead of print]114 112114

Development and application of the Cancer Cachexia Staging Index for the diagnosis and staging of cancer cachexia.

Junjie Wang, Shanjun Tan, Jiahao Xu, Shuhao Li, Mingyue Yan, Fan Yang, Qiuyue Huang, Zhige Zhang, Yanni Zhang, Jun Han, Hao Liu, Qiulin Zhuang, Qiulei Xi, Qingyang Meng, Guohao Wu.

OBJECTIVE: The current tools for evaluating cancer cachexia are either too simple to reflect the far-reaching effects of cachexia or too complicated to be used in daily practice. This study aimed to develop a cancer cachexia staging index (CCSI) that is both practical and comprehensive.
METHODS: Patients with gastrointestinal cancers were prospectively included in the study. Clinical data including weight change, body composition, systematic inflammation, nutrition, and function status were entered into regression models to determine the best variable combination as well as their respective cutoff values and score distribution in the CCSI. The CCSI's ability to predict outcomes and evaluate the consequences of cachexia for patients were then assessed.
RESULTS: Clinical information and test results from 10 568 patients were used to develop a CCSI composed of subjective and objective measures. Subjective measures included body mass index-adjusted weight loss grade, rate of weight loss, inflammation (neutrophil-to-lymphocyte ratio and C-reactive protein level), and prealbumin level. Objective measures included appetite status and physical status. Patients were diagnosed and stratified by the total CCSI score into 3 subgroups: no cachexia, mild or moderate cachexia, and severe cachexia. The CCSI grades showed good survival discrimination and were independently predictive of survival in multivariate analysis. Compared with the traditional Fearon criteria for diagnosing cancer cachexia, the CCSI was more accurate in predicting postoperative complications (net reclassification index [NRI], 2.8%; 95% CI, 0.0104-0.0456%), death (NRI, 10.68%; 95% CI, 0.0429-0.1708%), recurrence (NRI, 3.71%; 95% CI, 0.0082-0.0685%), and overall survival (NRI, 8.5%; 95% CI, 0.0219-0.1533%). The CCSI also had better discriminative ability than Fearon criteria in discriminating nutritional status, body composition, and systematic inflammation in patients with or without cachexia. A more detailed evaluation of a randomly selected subgroup (n = 1566) showed that CCSI grades had good discrimination of appetite and food intake status, physical function and muscle strength, symptom burden, and quality of life.
CONCLUSIONS: The CCSI is a comprehensive and practical evaluation tool for cancer cachexia. It can predict postoperative outcomes and survival. The CCSI stages showed good discrimination when evaluating patients with cancer in terms of nutritional status, physical function, systematic inflammation, body composition, symptom burden, and quality of life.

Keywords: Cancer cachexia; Classification; Diagnosis; Outcome

DOI: https://doi.org/10.1016/j.nut.2023.112114

Cell Death Dis. 2023 07 17. 14(7): 441

Bcl-2 family inhibitors sensitize human cancer models to therapy.

BH3 mimetics, targeting the Bcl-2 family anti-apoptotic proteins, represent a promising therapeutic opportunity in cancers. ABT-199, the first specific Bcl-2 inhibitor, was approved by FDA for the treatment of several hematological malignancies. We have recently discovered IS21, a novel pan BH3 mimetic with preclinical antitumor activity in several tumor types. Here, we evaluated the efficacy of IS21 and other BH3 mimetics, both as single agents and combined with the currently used antineoplastic agents in T-cell acute lymphoblastic leukemia, ovarian cancer, and melanoma. IS21 was found to be active in T-cell acute lymphoblastic leukemia, melanoma, lung, pancreatic, and ovarian cancer cell lines. Bcl-xL and Mcl-1 protein levels predicted IS21 sensitivity in melanoma and ovarian cancer, respectively. Exploring IS21 mechanism of action, we found that IS21 activity depends on the presence of BAX and BAK proteins: complexes between Bcl-2 and Bcl-xL proteins and their main binding partners were reduced after IS21 treatment. In combination experiments, BH3 mimetics sensitized leukemia cells to chemotherapy, ovarian cancer cells and melanoma models to PARP and MAPK inhibitors, respectively. We showed that this enhancing effect was related to the potentiation of the apoptotic pathway, both in hematologic and solid tumors. In conclusion, our data suggest the use of inhibitors of anti-apoptotic proteins as a therapeutic strategy to enhance the efficacy of anticancer treatment.

DOI: https://doi.org/10.1038/s41419-023-05963-1

Cell Signal. 2023 Jul 17. pii: S0898-6568(23)00220-6. [Epub ahead of print] 110806

The PRX-1/TLR4 axis promotes hypoxia-induced radiotherapy resistance in non-small cell lung cancer by targeting the NF-κB/p65 pathway.

Jiaojiao Hao, Zhuo Song, Jiayi Su, Longjie Li, Lijian Zou, Kun Zou.

Hypoxic lung cancer cells are highly resistant to radiation. Peroxiredoxin-1 (PRX-1), a transcriptional coactivator that enhances the DNA-binding activity of serum reactive factor, has been identified as a target for radiotherapy sensitization, but the underlying molecular mechanism remains unclear. This study aimed to investigate the influence of PRX-1 on radiotherapy sensitivity in hypoxic tumors. Hypoxic lung cancer cells exhibited radiotherapy-resistant phenotypes after irradiation, including increased proliferation, DNA damage repair, cell migration, invasion and stemness. Radio-resistant hypoxic lung cancer cells showed high expression levels of PRX-1. Furthermore, we observed that PRX-1 bound to the promoter region of TRL4 (-300 to -600) and promoted its transcription and expression and that PRX-1/TRL4 activated the NF-κB/p65 signaling pathway. Increased radiotherapy resistance of hypoxic lung cancer cells increased their ability to proliferate, migrate, and maintain stemness in vivo and in vitro. These findings suggest that PRX-1/TRL4 could be used as a target for the treatment of radiotherapy-resistant lung cancer cells and further provide a theoretical basis for the clinical treatment of hypoxic lung cancer cells.

Keywords: Hypoxia; NSCLCs; PRX-1; Radiotherapy resistance; TRL4

DOI: https://doi.org/10.1016/j.cellsig.2023.110806