bims-meluca Biomed News
on Metabolism of non-small cell lung carcinoma
Issue of 2024–10–06
nine papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge



  1. Technol Cancer Res Treat. 2024 Jan-Dec;23:23 15330338241282080
       BACKGROUND: Abnormal mitochondrial pyruvate carrier 1 (MPC1) expression plays a key role in tumor metabolic reprogramming and progression. Understanding its significance in non-small cell lung cancer (NSCLC) is crucial for identifying therapeutic targets.
    METHODS: TIMER 2.0 was utilized to assess the expression of MPC1 in both normal and cancer tissues in pan-cancer. Overall survival (OS) differences between high and low MPC1 expression were analyzed in NSCLC using the Cancer Genome Atlas (TCGA) datasets. We also examined the expression of MPC1 in NSCLC cell lines using western blotting and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). In addition, the tissue samples and clinical information of 80 patients with NSCLC from our hospital were collected. Immunohistochemistry (IHC) was used to assess MPC1 expression, and OS was evaluated using Kaplan-Meier curves and the log-rank test. Univariate and multivariate Cox regression analyses were conducted to evaluate the prognostic values of the clinical characteristics and MPC1expression.
    RESULTS: Analysis of public databases suggested that MPC1 was downregulated in NSCLC compared to that in normal lung tissue and predicted poor prognosis. In addition, the expression of MPC1 in NSCLC cell lines was lower than that in human bronchial epithelial (HBE) cells at both protein and mRNA levels. Further clinical analysis suggested that MPC1 expression was correlated with age, tumor T stage, and TNM stage. Kaplan-Meier analysis revealed that NSCLC patients with high MPC1 expression had a better prognosis, particularly in lung adenocarcinoma (LUAD), whereas no survival benefit was observed in lung squamous cell carcinoma (LUSC). Univariate and multivariate analyses suggested that MPC1 was an independent prognostic factor for patients with NSCLC.
    CONCLUSIONS: MPC1 is poorly expressed in NSCLC, particularly in LUAD, which predicts a poor prognosis and may serve as an independent prognostic factor. Further studies on MPC1 may reveal new targets for the treatment of NSCLC.
    Keywords:  lung adenocarcinoma (LUAD); mitochondrial pyruvate carrier 1 (MPC1); non-small cell lung cancer (NSCLC); overall survival (OS); prognosis
    DOI:  https://doi.org/10.1177/15330338241282080
  2. Farm Hosp. 2024 Oct 01. pii: S1130-6343(24)00151-X. [Epub ahead of print]
       OBJECTIVE: The expression level of programmed death ligand 1 (PD-L1) is the only approved biomarker for predicting response to immunotherapy, yet its efficacy is not always consistent. Lactate dehydrogenase (LDH) has been associated with tumor aggressiveness and poorer prognosis across various cancer types and may serve as a useful biomarker for monitoring treatment response. The objective of this study is to analyze the relationship between LDH levels prior to the start of treatment with immune checkpoint inhibitors (ICIs) and clinical outcomes in patients with non-small cell lung cancer (NSCLC).
    METHOD: A retrospective study was conducted including patients diagnosed with NSCLC who were treated with at least three cycles of immunotherapy. Data on demographics, clinical and pathological characteristics, treatment received, pre-treatment LDH levels, and clinical outcomes such as treatment response and overall survival (OS) were analyzed.
    RESULTS: A total of 181 patients diagnosed with NSCLC were included. Elevated pre-treatment LDH levels (more than 244 U/l) were associated with significantly reduced OS. The median survival was 548 days in patients with LDH less than 244 U/l, compared to 332 days in those with LDH more than 244 U/l (p = 0.037). Among men, OS was greater in the LDH less than 244 U/l group (623 days) versus 332 days in the LDH more than 244 U/l group (p = 0.043). In patients with metastatic disease, OS was higher in those with LDH less than 244 U/l (474 days) compared to 249 days in those with LDH more than 244 U/l (p = 0.023). In patients receiving both immunotherapy and chemotherapy, OS was greater in those with LDH less than 244 U/l (623 days) compared to 281 days in the LDH more than 244 U/l group (p = 0.042).
    CONCLUSIONS: High levels of LDH prior to the start of treatment with ICIs are associated with lower treatment efficacy and a worse prognosis of the disease, especially in male, metastatic patients with a PD-L1 expression level less than 1%.
    Keywords:  Biomarcadores; Biomarkers; Cáncer de pulmón no microcítico; Immunotherapy; Inmunoterapia; Lactate dehydrogenase; Lactato deshidrogenasa; Non-small cell lung cancer; Supervivencia; Survival
    DOI:  https://doi.org/10.1016/j.farma.2024.09.003
  3. Nagoya J Med Sci. 2024 Aug;86(3): 452-463
      The presence of anti-thyroid antibodies (ATAs) is a biomarker for the development of thyroid dysfunction induced by anti-programmed cell death-1 antibodies (PD-1-Abs). While patients with thyroid dysfunction reportedly showed better overall survival (OS), it remains unknown if ATAs at baseline can predict OS. Therefore, in this study, we examined the association of ATAs at baseline with OS in non-small cell lung cancer (NSCLC) patients with different levels of programmed cell death-1 ligand 1 (PD-L1) positivity associated with PD-1-Ab treatment efficacy. A total of 81 NSCLC patients treated with PD-1-Abs were evaluated for ATAs at baseline and prospectively for OS. Among the 81 patients, 49 and 32 patients had ≥50% (group A) and <50% (group B) PD-L1 positivity, respectively. Median OS did not differ significantly between patients with (n = 13) and without (n = 36) ATAs at baseline in group A. In contrast, median OS was significantly longer in patients with (n = 10) versus without (n = 22) ATAs at baseline in group B (not reached vs 378 days, respectively; 95% CI, 182 to 574 days, p = 0.049). These findings suggest that the presence of ATAs at baseline is a biomarker to predict better treatment efficacy of PD-1-Abs in NSCLC patients with low PD-L1 positivity, while the difference in OS in those with high PD-L1 positivity may be masked by increased tumor expression of PD-L1.
    Keywords:  autoimmunity; biomarkers; lung neoplasms; programmed cell death-1 (PD-1); thyroid
    DOI:  https://doi.org/10.18999/nagjms.86.3.452
  4. Mol Biol Rep. 2024 Oct 03. 51(1): 1036
       BACKGROUND: Lung cancer is recognized as one of the leading causes of cancer-related deaths globally, with a significant increase in incidence and intricate pathogenic mechanisms. This study examines the expression profiles of Programmed Cell Death Protein 1 (PD-1), PD-1 ligand (PDL-1), β-catenin, CD44, interleukin 6 (IL-6), and interleukin 10 (IL-10), as well as their correlations with the clinic-pathological features and diagnostic significance in lung cancer patients.
    METHODS AND RESULTS: The research involved lung cancer patients exhibiting various pathological characteristics, alongside demographically matched healthy controls. The expression levels of PD-1, PDL-1, β-catenin, and CD44 were analyzed using Real-Time PCR, while circulating levels of IL-6 and IL-10 were assessed through ELISA assays. This investigation focused on peripheral blood mononuclear cells (PBMC) to evaluate these factors non-invasively. Findings indicated that levels of PD-1, PDL-1, and CD44 were significantly elevated in patients compared to controls, which coincided with a decrease in β-catenin levels. Additionally, a concurrent rise in IL-6 and IL-10, both pro-inflammatory cytokines, was observed in patients, suggesting a potential regulatory role for these cytokines on the PD-1/PDL-1 axis, which may help tumors evade immune system checkpoints. The predictive value of these factors concerning lung tumors and metastasis was significant (Regression analysis). Furthermore, these markers demonstrated diagnostic potential in differentiating between patients and healthy controls, as well as between individuals with metastatic and non-metastatic tumors (ROC curve analysis).
    CONCLUSIONS: This study provides insights into the expression profiles of PD-1/PDL-1 immune system checkpoints and their regulatory factors in lung cancer, potentially paving the way for new therapeutic and diagnostic approaches.
    Keywords:  CD44; Interleukin 10; Interleukin 6; Lung cancer; PD-1; PDL-1; Β-catenin
    DOI:  https://doi.org/10.1007/s11033-024-09971-y
  5. PLoS One. 2024 ;19(10): e0297397
      The insulin-like growth factor 1 receptor (IGF1R) has been associated with growth and metastasis in various cancers. However, its role in postoperative recurrence and prognosis in lung cancer lacks clear consensus. Therefore, this study aimed to investigate the potential relationship between IGF1R and postoperative recurrence as well as long-term survival in a large cohort. Additionally, we assessed the relationship between IGF1R and programmed death ligand 1 (PD-L1) expression. Our study encompassed 782 patients with non-small cell lung cancer (NSCLC). Immunostaining of surgical specimens was performed to evaluate IGF1R and PD-L1 expression. Among the patients, 279 (35.8%) showed positive IGF1R expression, with significantly worse relapse-free survival (RFS) and overall survival (OS). Notably, no significant differences in RFS and OS were observed between IGF1R-positive and -negative groups in stages 2 and 3. However, in the early stages (0-1), the positive group displayed significantly worse RFS and OS. In addition, PD-L1 expression was detected in 100 (12.8%) patients, with a significant predominance in the IGF1R-positive. IGF1R may serve as a prognostic indicator and a guide for perioperative treatment strategies in early-stage lung cancer. In conclusion, our findings underscore an association between IGF1R expression and poor survival and PD-L1 expression in NSCLC.
    DOI:  https://doi.org/10.1371/journal.pone.0297397
  6. Int J Obes (Lond). 2024 Oct 03.
       BACKGROUND: The impact of weight loss on survival outcomes remains challenging in patients with lung cancer. The objective of this systematic review with meta-analysis was to assess the association of weight loss with survival outcomes in these patients.
    METHODS: Two authors conducted a comprehensive literature search of PubMed, Web of Science, and Embase databases up to January 15, 2024. Observational studies that assessed the weight loss as a prognostic factor of overall survival and progression-free survival in patients with lung cancer were included this analysis. Weight loss defined by at least 5% loss of total body weight over 2 months.
    RESULTS: Fifteen studies involving 14,540 patients with lung cancer were included. Pooled adjusted hazard ratios (HR) indicated that weight loss was associated with reduced overall survival (HR 1.65; 95% confidence intervals [CI] 1.43-1.91) and progression-free survival (HR 1.40; 95% CI 1.15-1.71). Subgroup analysis showed that weight loss significantly predicted overall survival, regardless of study design, lung cancer subtypes, clinical stage of cancer, weight loss definition, or length of follow-up.
    CONCLUSIONS: Weight loss is a significant predictor of overall survival and progression-free survival in patients with lung cancer. Weight monitoring has potential to improve prognostication of survival outcomes for these patients.
    DOI:  https://doi.org/10.1038/s41366-024-01642-z
  7. J Cachexia Sarcopenia Muscle. 2024 Oct 01.
       BACKGROUND: Cancer cachexia complicates advanced non-small cell lung cancer (NSCLC); however, it remains unclear how often cachexia occurs and how it affects the course of chemotherapy in patients receiving first-line systemic therapy.
    METHODS: We conducted a multicentre, prospective observational study and enrolled previously untreated NSCLC patients with Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-2 and cachexia between September 2020 and September 2021. The primary outcome measure was the trends in the Functional Assessment of Anorexia/Cachexia Treatment and Anorexia/Cachexia Subscale [FAACT (A/CS)] scores by cohort. Secondary outcome measures included the incidence of cachexia before the initiation of first-line systemic therapy, quality of life (QOL) measures, body weight (BW) changes, and efficacy and safety of first-line systemic therapy.
    RESULTS: A total of 887 consecutive patients with previously untreated advanced NSCLC and ECOG PS of 0-2 who were initiated on first-line systemic therapy were evaluated. A total of 281 patients (31.7%) experienced BW loss consistent with the criteria of cachexia, and 186 were evaluated for QOL, BW and outcome measurements. Overall, 180/186 patients received first-line systemic therapy. Cohort 1 (targeted therapy), cohort 2 [cytotoxic chemotherapy (CTx) ± immune checkpoint inhibitors (ICIs)] and cohort 3 (ICIs) included 42, 98 and 40 patients, respectively. There were significant variations in QOL trends by cohort, with chemotherapy-associated emesis affecting early appetite-related QOL. The change in the FAACT (A/CS) score at 1 week from baseline was worse in cohort 2 (the least square mean change ± standard error: -3.0 ± 0.9) than in cohorts 1 (1.6 ± 1.2, p = 0.003) and 3 (1.8 ± 1.0, p = 0.002); meanwhile, the change at 6 weeks was worse in cohort 1 (-1.5 ± 1.2) than in cohorts 2 (3.6 ± 0.9, p = 0.001) and 3 (3.5 ± 1.1, p = 0.004). BW reduction was observed in all cohorts within 6 weeks of therapy initiation. The targeted therapy cohort demonstrated superior progression-free survival (PFS) and overall survival (OS) to CTx ± ICIs cohort or ICIs cohort (median PFS was 9.7 months, 6.3 months, 3.1 months, in cohort 1, 2, 3, respectively (cohort 1 vs. cohort 2: HR, 0.58, p = 0.018; cohort 1 vs. cohort 3: HR, 0.41, p = 0.001); median OS was not reached, 15.8 months, 9.9 months, respectively (cohort 1 vs. cohort 2: HR, 0.52, p = 0.033; cohort 1 vs. cohort 3: HR, 0.37, p = 0.003).
    CONCLUSIONS: Approximately 1/3 patients with previously untreated advanced NSCLC have cachexia. Appetite-related QOL trends vary based on the type of first-line systemic therapy in cachectic NSCLC patients, and the PFS and OS of these patients seemed to be shorter.
    Keywords:  anorexia; cancer cachexia; non‐small cell lung cancer; quality of life
    DOI:  https://doi.org/10.1002/jcsm.13606
  8. Anticancer Res. 2024 Oct;44(10): 4493-4503
       BACKGROUND/AIM: The aim of the study was to develop a novel predictive scoring system based on the dynamics of serum inflammatory indicators in immune checkpoint inhibitor (ICI) treatment on non-small-cell lung cancer (NSCLC) with bone metastases.
    PATIENTS AND METHODS: Sixty patients with NSCLC and bone metastases treated with ICIs between January 2016 and March 2021 were included in the development cohort. Serum neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP) levels were assessed before (pre-value) and 6 weeks after (post-value) ICI treatment, and a novel predictive score was developed: pre-value ≥ post-value, 0 points; pre-value < post-value, 1 point; total score: 0-2 points. The associations of these dynamics and the score with clinical outcomes, including overall survival (OS), progression-free survival (PFS), response rate (RR) of bone metastases, and disease control rate (DCR), were evaluated. Furthermore, cross-validation was performed with 23 patients after April 2021 using the same inclusion criteria.
    RESULTS: The patients with decreased serum inflammation levels had significantly better OS, PFS, and RR than those with increased levels. Applying the developed score to the development cohort, the patients with 0 points had significantly better OS, PFS, and RR than others. In multivariable analysis, the score independently predicted treatment response to ICI for bone metastasis and prognosis. Cross-validation showed that OS, PFS, and RR were significantly better in the patients in the 0-point group.
    CONCLUSION: The early NLR and CRP dynamics were associated with therapeutic responses to ICIs in NSCLC with bone metastases. Our novel scoring system based on these dynamics is simple and has a high predictive accuracy.
    Keywords:  Non-small-cell lung cancer; bone metastasis; c-reactive protein; immune checkpoint inhibitor; neutrophil-to-lymphocyte ratio
    DOI:  https://doi.org/10.21873/anticanres.17278
  9. Clin Transl Med. 2024 Oct;14(10): e70037
       BACKGROUND: The transcription factor NRF2 plays a significant role in regulating genes that protect cells from oxidative damage. O-GlcNAc modification, a type of posttranslational modification, is crucial for cellular response to stress. Although the involvement of both NRF2 and O-GlcNAc in maintaining cellular redox balance and promoting cancer malignancy has been demonstrated, the potential mechanisms remain elusive.
    METHODS: The immunoblotting, luciferase reporter, ROS assay, co-immunoprecipitation, and immunofluorescence was used to detect the effects of global cellular O-GlcNAcylation on NRF2. Mass spectrometry was utilised to map the O-GlcNAcylation sites on NRF2, which was validated by site-specific mutagenesis and O-GlcNAc enzymatic labelling. Human lung cancer samples were employed to verify the association between O-GlcNAc and NRF2. Subsequently, the impact of NRF2 O-GlcNAcylation in lung cancer malignancy and cisplatin resistance were evaluated in vitro and in vivo.
    RESULTS: NRF2 is O-GlcNAcylated at Ser103 residue, which hinders its binding to KEAP1 and thus enhances its stability, nuclear localisation, and transcription activity. Oxidative stress and cisplatin can elevate the phosphorylation of OGT at Thr444 through the activation of AMPK kinase, leading to enhanced binding of OGT to NRF2 and subsequent elevation of NRF2 O-GlcNAcylation. Both in cellular and xenograft mouse models, O-GlcNAcylation of NRF2 at Ser103 promotes the malignancy of lung cancer. In human lung cancer tissue samples, there was a significant increase in global O-GlcNAcylation, and elevated levels of NRF2 and its O-GlcNAcylation compared to paired adjacent normal tissues. Chemotherapy promotes NRF2 O-GlcNAcylation, which in turn decreases cellular ROS levels and drives lung cancer cell survival.
    CONCLUSION: Our findings indicate that OGT O-GlcNAcylates NRF2 at Ser103, and this modification plays a role in cellular antioxidant, lung cancer malignancy, and cisplatin resistance.
    Keywords:  NRF2; O‐GlcNAc; ROS; drug resistance; lung cancer
    DOI:  https://doi.org/10.1002/ctm2.70037