bims-meluca Biomed News
on Metabolism of non-small cell lung carcinoma
Issue of 2024‒02‒25
nine papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge
  1. Metabolic Responses of Lung Adenocarcinoma Cells to Survive under Stressful Conditions Associated with Tumor Microenvironment.
  2. Plasma sPD-L1 and VEGF levels are associated with the prognosis of NSCLC patients treated with combination immunotherapy.
  3. Neutrophil to lymphocyte ratio may predict efficacy of anti-PD-1 inhibitors in advanced EGFR-mutant non-small cell lung cancer: retrospective cohort study.
  4. Correlation between PD-L1 expression status and efficacy of immunotherapy as second-line or later-line therapy in advanced non-small cell lung cancer patients.
  5. Identification and Validation of a Hypoxia and Glycolysis Prognostic Signatures in Lung Adenocarcinoma.
  6. Effects of different KRAS mutants and Ki67 expression on diagnosis and prognosis in lung adenocarcinoma.
  7. Drug Response of Patient-Derived Lung Cancer Cells Predicts Clinical Outcomes of Targeted Therapy.
  8. Detailed Characterization of the Lung-Gut Microbiome Axis Reveals the Link between PD-L1 and the Microbiome in Non-Small-Cell Lung Cancer Patients.
  9. Exploring the Molecular Tumor Microenvironment and Translational Biomarkers in Brain Metastases of Non-Small-Cell Lung Cancer.
  1. Metabolites. 2024 Feb 02. pii: 103. [Epub ahead of print]14(2):
    Metabolic Responses of Lung Adenocarcinoma Cells to Survive under Stressful Conditions Associated with Tumor Microenvironment.
    Angeles Carlos-Reyes, Susana Romero-Garcia, Heriberto Prado-Garcia.
      Solid tumors frequently present a heterogeneous tumor microenvironment. Because tumors have the potential to proliferate quickly, the consequence is a reduction in the nutrients, a reduction in the pH (<6.8), and a hypoxic environment. Although it is often assumed that tumor clones show a similar growth rate with little variations in nutrient consumption, the present study shows how growth-specific rate (µ), the specific rates of glucose, lactate, and glutamine consumption (qS), and the specific rates of lactate and glutamate production (qP) of 2D-cultured lung tumor cells are affected by changes in their environment. We determined in lung tumor cells (A427, A549, Calu-1, and SKMES-1) the above mentioned kinetic parameters during the exponential phase under different culture conditions, varying the predominant carbon source, pH, and oxygen tension. MCF-7 cells, a breast tumor cell line that can consume lactate, and non-transformed fibroblast cells (MRC-5) were included as controls. We also analyzed how cell-cycle progression and the amino acid transporter CD98 expression were affected. Our results show that: (1) In glucose presence, μ increased, but qS Glucose and qP Lactate decreased when tumor cells were cultured under acidosis as opposed to neutral conditions; (2) most lung cancer cell lines consumed lactate under normoxia or hypoxia; (3) although qS Glutamine diminished under hypoxia or acidosis, it slightly increased in lactate presence, a finding that was associated with CD98 upregulation; and (4) under acidosis, G0/G1 arrest was induced in A427 cancer cells, although this phenomenon was significantly increased when glucose was changed by lactate as the predominant carbon-source. Hence, our results provide an understanding of metabolic responses that tumor cells develop to survive under stressful conditions, providing clues for developing promising opportunities to improve traditional cancer therapies.
    Keywords:  glucose deprivation; hypoxia; lactic acidosis; specific growth rate; tumor metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3390/metabo14020103
  2. Anticancer Drugs. 2024 Feb 23.
    Plasma sPD-L1 and VEGF levels are associated with the prognosis of NSCLC patients treated with combination immunotherapy.
    Changhong Dong, Kaiyuan Hui, Jie Gu, Mei Wang, Chenxi Hu, Xiaodong Jiang.
      The clinical significance of plasma soluble programmed cell death ligand 1 (sPD-L1) and vascular endothelial growth factor (VEGF) for non-small cell lung cancer (NSCLC) treated with the combination of anti-angiogenic therapy and anti-PD-L1 antibody (Ab) remain unknown. This study aimed to explore the association between plasma sPD-L1 and VEGF levels and the prognosis of NSCLC patients treated with the combination of Envafolimab and Endostar. Peripheral blood samples were collected from 24 NSCLC patients at baseline and after 6 weeks of treatment and were detected for sPD-L1 and VEGF levels. Both baseline and posttreatment sPD-L1 were significantly higher in progressive disease (PD) group than in controlled disease (CD) group (median: 77.5 pg/ml vs. 64.6 pg/ml, P = 0.036, median: 8451 pg/ml vs. 5563 pg/ml, P = 0.012). In multivariate analysis, lower baseline sPD-L1 levels were significantly associated with longer progression-free survival (PFS) (HR = 6.834, 95% CI: 1.350-34.592, P = 0.020). There were significantly higher posttreatment VEGF levels in PD group compared with CD group (median: 323.7 pg/ml vs. 178.5 pg/ml, P = 0.009). Higher posttreatment VEGF levels were significantly associated with shorter PFS in multivariate analysis (HR = 5.911, 95% CI: 1.391-25.122, P = 0.016). Plasma sPD-L1 and VEGF levels are associated with the clinical response and prognosis of NSCLC patients treated with the combination of PD-L1 inhibitors and anti-angiogenetic therapy.
    DOI:  https://doi.org/10.1097/CAD.0000000000001576
  3. Sci Rep. 2024 02 20. 14(1): 4165
    Neutrophil to lymphocyte ratio may predict efficacy of anti-PD-1 inhibitors in advanced EGFR-mutant non-small cell lung cancer: retrospective cohort study.
    Jianxin Chen, Qinhong Zheng, Shijian Zhu, Dan Qiu, Junhui Wang.
      This study aimed to investigate the associations between the clinical characteristics and effectiveness of anti-PD-1 inhibitors in patients with EGFR-sensitive mutations, aiming to identify the potential subgroup of patients who might benefit from anti-PD-1 inhibitor treatment. Patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR)-sensitive mutations who received subsequent anti-PD-1 inhibitors in combination with chemotherapy/antiangiogenic agents or alone after progression to tyrosine kinase inhibitors (TKIs) were screened. Clinical characteristics, including hematological parameters, were investigated for potential correlations with clinical outcomes. Subgroup and multivariate analyses were used for further confirmation of the relationship. Kaplan-Meier curves and Cox survival regression models using the log-rank test were used for progression-free survival (PFS) and overall survival (OS) assessments between the groups. Multiple regression analysis was performed using the standard regression coefficient values. The Wilcoxon test was used for the analysis of the variation in NLR. P ≤ 0.05 was considered to indicate statistical significance. This study was a retrospective study. Twenty-two patients met the inclusion criteria and were included in the study. The median PFS was 3.05 months (95% CI, 2.9-10.2 months). The median OS was 7.30 months (95% CI, 5.2-18.1 months). PFS in low neutrophil to lymphocyte ratio (NLR ≤ 4) was significantly longer than high NLR (NLR > 4, 5.7 months versus 2.0 months, HR, 0.35, 95% CI, 0.08-0.63, P = 0.0083). The OS in the low NLR group was also significantly better than that in the high NLR group (OS, 21.3 months versus 5.0 months, HR, 0.33; 95% CI, 0.09-0.74; P = 0.0163). In the multivariate analysis, NLR was the only significant factor for OS benefits (β = 3.535, 95% CI, 1.175-10.636, P = 0.025). Further investigation revealed that front-line TKIs exposure may contribute to the elevation or decrease of NLR, and finally lead to different efficacy outcomes by anti-PD-1 inhibitors. The findings suggest that a portion of advanced NSCLC patients with low NLR characteristics (NLR ≤ 4), even those harboring EGFR-sensitive mutations, could benefit from anti-PD-1 inhibitors as further line treatment after progression to EGFR-TKIs.
    Keywords:  Anti-PD-1 inhibitor; Efficacy; Epidermal growth factor receptor; Neutrophil to lymphocyte ratio; Non-small cell lung cancer
    DOI:  https://doi.org/10.1038/s41598-024-54557-0
  4. Eur J Cancer Prev. 2024 Feb 23.
    Correlation between PD-L1 expression status and efficacy of immunotherapy as second-line or later-line therapy in advanced non-small cell lung cancer patients.
    Jingya Liu, Yingchun Man, Jianing Gao, Xinxin Wang, Lijie Zhang, Mingheng Li, Jiahan Yu.
      OBJECTIVE: The objective of this study is to evaluate the correlation between tumor proportionality scores (TPS) and the effectiveness of immune checkpoint inhibitors (ICIs) as the second or subsequent line therapies for individuals who received diagnoses of advanced non-small cell lung cancer (NSCLC).METHODS: The retrospective analysis was conducted on the medical records of a total of 143 patients who received diagnoses of stage IIIB/IV NSCLC and were admitted to our hospital from the beginning of 2019 to the end of September 2022. The follow-up period ended on 01 January 2023. The study used Kaplan-Meier survival curves to assess the progression-free survival (PFS) and overall survival (OS) of patients. Univariate and multivariate Cox proportional risk models were used to analyze the factors associated with the PFS and OS of advanced-stage NSCLC patients who received ICIs as the second or subsequent lines.
    RESULTS: Patients diagnosed with NSCLC who had a TPS ≥1% and got treatment with ICIs exhibit notably elevated rates of partial response, objective response rate, disease control rate and extended PFS in comparison to NSCLC patients with a TPS of <1% (P < 0.05). NSCLC patients with TPS within 1-49% [hazard ratio (HR) = 0.372; 95% confidence interval (CI), 0.140-0.993; P = 0.048] or ≥50% (HR = 0.276; 95% CI, 0.095-0.796; P = 0.017) were significantly associated with prolonged PFS, which were conducted by multivariate Cox regression analysis.
    CONCLUSION: Programmed death protein-1 expression status may be predictive markers of the effectiveness of ICIs as the second or subsequent lines of therapies in advanced NSCLC are influenced by TPS.
    DOI:  https://doi.org/10.1097/CEJ.0000000000000880
  5. J Cancer. 2024 ;15(6): 1568-1582
    Identification and Validation of a Hypoxia and Glycolysis Prognostic Signatures in Lung Adenocarcinoma.
    Wenhao Zhao, Chen Ding, Meiru Zhao, Yongwen Li, Hua Huang, Xuanguang Li, Qian Cheng, Zijian Shi, Weining Gao, Hongyu Liu, Jun Chen.
      Background: Lung adenocarcinoma (LUAD) represents a prevalent subtype of non-small cell lung cancer with a complex molecular landscape. Dysregulated cellular energetics, notably the interplay between hypoxia and glycolysis, has emerged as a hallmark feature of LUAD tumorigenesis and progression. In this study, we aimed to identify hypoxia and glycolysis related gene signatures and construct a prognostic model to enhance the clinical management of LUAD. Methods: A gene signature associated with hypoxia and glycolysis was established within the The Cancer Genome Atlas (TCGA) cohort and subsequently validated in the GSE31210 cohort. Additionally, a nomogram was formulated to aid in predictive modeling. Subsequently, an evaluation of the tumor microenvironment and immune checkpoints expression levels was conducted to discern disparities between low risk and high risk groups. Lastly, an exploration for drugs with potential effectiveness was carried out. Results: Our analyses revealed a distinct hypoxia and glycolysis related gene signature consisting of 6 genes significantly associated with LUAD patient survival. Integration of these genes into the prognostic model demonstrated superior predictive accuracy for patient outcomes. Furthermore, we developed a user-friendly nomogram that effectively translates the model's prognostic information into a practical tool for clinical decision-making. Conclusion: This study elucidates the critical role of hypoxia and glycolysis related genes in LUAD and offers a novel prognostic model with promising clinical utility. This model has the potential to refine risk stratification and guide personalized therapeutic interventions, ultimately improving the prognosis of LUAD patients.
    Keywords:  glycolysis; hypoxia; immune; immunotherapy.; lung adenocarcinoma; prognosis
    DOI:  https://doi.org/10.7150/jca.91504
  6. Sci Rep. 2024 02 19. 14(1): 4085
    Effects of different KRAS mutants and Ki67 expression on diagnosis and prognosis in lung adenocarcinoma.
    Jun Wang, Liwen Dong, Zhaowei Zheng, Zhen Zhu, Baisheng Xie, Yue Xie, Xiongwei Li, Bing Chen, Pan Li.
      Lung adenocarcinoma (LUAD) is a prevalent form of non-small cell lung cancer with a rising incidence in recent years. Understanding the mutation characteristics of LUAD is crucial for effective treatment and prediction of this disease. Among the various mutations observed in LUAD, KRAS mutations are particularly common. Different subtypes of KRAS mutations can activate the Ras signaling pathway to varying degrees, potentially influencing the pathogenesis and prognosis of LUAD. This study aims to investigate the relationship between different KRAS mutation subtypes and the pathogenesis and prognosis of LUAD. A total of 63 clinical samples of LUAD were collected for this study. The samples were analyzed using targeted gene sequencing panels to obtain sequencing data. To complement the dataset, additional clinical and sequencing data were obtained from TCGA and MSK. The analysis revealed significantly higher Ki67 immunohistochemical scores in patients with missense mutations compared to controls. Moreover, the expression level of KRAS was found to be significantly correlated with Ki67 expression. Enrichment analysis indicated that KRAS missense mutations activated the SWEET_LUNG_CANCER_KRAS_DN and CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_2 pathways. Additionally, patients with KRAS missense mutations and high Ki67 IHC scores exhibited significantly higher tumor mutational burden levels compared to other groups, which suggests they are more likely to be responsive to ICIs. Based on the data from MSK and TCGA, it was observed that patients with KRAS missense mutations had shorter survival compared to controls, and Ki67 expression level could more accurately predict patient prognosis. In conclusion, when utilizing KRAS mutations as biomarkers for the treatment and prediction of LUAD, it is important to consider the specific KRAS mutant subtypes and Ki67 expression levels. These findings contribute to a better understanding of LUAD and have implications for personalized therapeutic approaches in the management of this disease.
    DOI:  https://doi.org/10.1038/s41598-023-48307-x
  7. Cancers (Basel). 2024 Feb 14. pii: 778. [Epub ahead of print]16(4):
    Drug Response of Patient-Derived Lung Cancer Cells Predicts Clinical Outcomes of Targeted Therapy.
    Sunshin Kim, Youngjoo Lee, Bo Ram Song, Hanna Sim, Eun Hye Kang, Mihwa Hwang, Namhee Yu, Sehwa Hong, Charny Park, Beung-Chul Ahn, Eun Jin Lim, Kum Hui Hwang, Seog-Yun Park, Jin-Ho Choi, Geon Kook Lee, Ji-Youn Han.
      Intratumor heterogeneity leads to different responses to targeted therapies, even within patients whose tumors harbor identical driver oncogenes. This study examined clinical outcomes according to a patient-derived cell (PDC)-based drug sensitivity test in lung cancer patients treated with targeted therapies. From 487 lung cancers, 397 PDCs were established with a success rate of 82%. In 139 PDCs from advanced non-small-cell lung cancer (NSCLC) patients receiving targeted therapies, the standardized area under the curve (AUC) values for the drugs was significantly correlated with their tumor response (p = 0.002). Among 59 chemo-naive EGFR/ALK-positive NSCLC patients, the PDC non-responders showed a significantly inferior response rate (RR) and progression-free survival (PFS) for the targeted drugs than the PDC responders (RR, 25% vs. 78%, p = 0.011; median PFS, 3.4 months [95% confidence interval (CI), 2.8-4.1] vs. 11.8 months [95% CI, 6.5-17.0], p < 0.001). Of 25 EGFR-positive NSCLC patients re-challenged with EGFR inhibitors, the PDC responder showed a higher RR than the PDC non-responder (42% vs. 15%). Four patients with wild-type EGFR or uncommon EGFR-mutant NSCLC were treated with EGFR inhibitors based on their favorable PDC response to EGFR inhibitors, and two patients showed dramatic responses. Therefore, the PDC-based drug sensitivity test results were significantly associated with clinical outcomes in patients with EGFR- or ALK-positive NSCLC. It may be helpful for predicting individual heterogenous clinical outcomes beyond genomic alterations.
    Keywords:  ALK fusion; EGFR mutation; lung cancer; patient-derived cell; predictive marker; targeted therapy
    DOI:  https://doi.org/10.3390/cancers16040778
  8. Int J Mol Sci. 2024 Feb 15. pii: 2323. [Epub ahead of print]25(4):
    Detailed Characterization of the Lung-Gut Microbiome Axis Reveals the Link between PD-L1 and the Microbiome in Non-Small-Cell Lung Cancer Patients.
    Vytautas Ankudavicius, Darja Nikitina, Rokas Lukosevicius, Deimante Tilinde, Violeta Salteniene, Lina Poskiene, Skaidrius Miliauskas, Jurgita Skieceviciene, Marius Zemaitis, Juozas Kupcinskas.
      Next-generation sequencing technologies have started a new era of respiratory tract research in recent years. Alterations in the respiratory microbiome between healthy and malignant conditions have been revealed. However, the composition of the microbiome varies among studies, even in similar medical conditions. Also, there is a lack of complete knowledge about lung-gut microbiome interactions in lung cancer patients. The aim of this study was to explore the lung-gut axis in non-small-cell lung cancer (NSCLC) patients and the associations between lung-gut axis microbiota and clinical parameters (CRP, NLR, LPS, CD8, and PD-L1). Lung tissue and fecal samples were used for bacterial 16S rRNA sequencing. The results revealed, for the first time, that the bacterial richness in lung tumor tissue gradually decreased with an increase in the level of PD-L1 expression (p < 0.05). An analysis of β-diversity indicated a significant positive correlation between the genera Romboutsia and Alistipes in both the lung tumor biopsies and stool samples from NSCLC patients (p < 0.05). Survival analysis showed that NSCLC patients with higher bacterial richness in their stool samples had prolonged overall survival (HR: 2.06, 95% CI: 1.025-4.17, p = 0.0426).
    Keywords:  PD-L1; lung cancer; lung–gut axis; microbiota
    DOI:  https://doi.org/10.3390/ijms25042323
  9. Int J Mol Sci. 2024 Feb 07. pii: 2044. [Epub ahead of print]25(4):
    Exploring the Molecular Tumor Microenvironment and Translational Biomarkers in Brain Metastases of Non-Small-Cell Lung Cancer.
    Jiexi Wen, Jie-Zeng Yu, Catherine Liu, A Aziz O Ould Ismail, Weijie Ma.
      Brain metastases represent a significant clinical challenge in the treatment of non-small-cell lung cancer (NSCLC), often leading to a severe decline in patient prognosis and survival. Recent advances in imaging and systemic treatments have increased the detection rates of brain metastases, yet clinical outcomes remain dismal due to the complexity of the metastatic tumor microenvironment (TME) and the lack of specific biomarkers for early detection and targeted therapy. The intricate interplay between NSCLC tumor cells and the surrounding TME in brain metastases is pivotal, influencing tumor progression, immune evasion, and response to therapy. This underscores the necessity for a deeper understanding of the molecular underpinnings of brain metastases, tumor microenvironment, and the identification of actionable biomarkers that can inform multimodal treatment approaches. The goal of this review is to synthesize current insights into the TME and elucidate molecular mechanisms in NSCLC brain metastases. Furthermore, we will explore the promising horizon of emerging biomarkers, both tissue- and liquid-based, that hold the potential to radically transform the treatment strategies and the enhancement of patient outcomes.
    Keywords:  biomarker; brain metastases; molecular cancer; non-small-cell lung cancer; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms25042044
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