bims-meluca 2025-02-23 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2025–02–23
eight papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Predictive value of serum cytokines in patients with non-small-cell lung cancer receiving anti-PD-1 blockade therapy: a meta-analysis.
A CRISPR-edited isoform of the AMPK kinase LKB1 improves the response to cisplatin in A549 lung cancer cells.
Systemic Immune-Inflammation Index as a Predictor of Survival in Non-Small Cell Lung Cancer Patients Undergoing Immune Checkpoint Inhibition: A Systematic Review and Meta-Analysis.
A method for the identification of lactate metabolism-related prognostic biomarkers and its validations in non-small cell lung cancer.
SIRT6 Ameliorates Cancer Cachexia-Associated Adipose Wasting by Suppressing TNFR2 Signalling in Mice.
Significance of Neutrophil-to-Lymphocyte Ratio in Predicting the Efficacy of Anamorelin for Cancer Cachexia.
STK11 genetic alterations in metastatic EGFR mutant lung cancer.
PLCXD3-ALK, a novel ALK rearrangement in lung squamous cell carcinoma and its clinical responses to ALK inhibitors.

Clin Exp Med. 2025 Feb 16. 25(1): 59

Predictive value of serum cytokines in patients with non-small-cell lung cancer receiving anti-PD-1 blockade therapy: a meta-analysis.

Qian Liu, Zakari Shaibu, Aiguo Xu, Fang Yang, Ruoxue Cao, Fumeng Yang.

  Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide. Immunotherapy, particularly PD-1 inhibitors, has revolutionized the treatment landscape for NSCLC. However, the predictive biomarkers for PD-1 inhibitor therapy are still limited. Serum cytokines have emerged as potential biomarkers for predicting treatment outcomes. This meta-analysis aims to investigate the predictive value of serum cytokines in PD-1 inhibitor therapy for NSCLC. We conducted a comprehensive literature search in major databases, including PubMed, Google scholar, Embase, and Cochrane database, with a focus on literature published up until October 22, 2024. Studies investigating the association between serum cytokine levels and treatment outcomes in NSCLC patients receiving PD-1 inhibitor therapy were included. The primary outcomes were progression-free survival (PFS) and overall survival (OS). The meta-analysis revealed that elevated IL-6 levels were significantly associated with poorer PFS in NSCLC patients (HR = 2.30, 95% CI [1.39-3.80], P = 0.001). Additionally, high IL-10 expression was related to poorer PFS in NSCLC after therapy (HR = 2.45, 95% CI [1.26-4.76], P = 0.009). In contrast, no significant associations were found between OS and the expression of various cytokines, including IL-4, IL-5, IL-6, IL-8, IL-10, IFN-γ, IL-1β, TNF-α, and IL-12p70. This meta-analysis demonstrates that elevated IL-6 and IL-10 levels are significantly associated with poorer PFS in NSCLC patients receiving PD-1 inhibitor therapy. These findings suggest that serum cytokine levels may serve as predictive biomarkers for treatment outcomes. Further studies are needed to validate these results and explore the underlying mechanisms.

Keywords:  Cytokine biomarkers; Immunotherapy response; Non-small cell lung cancer; PD-1 inhibitor; Predictive biomarkers; Serum cytokines

DOI:  https://doi.org/10.1007/s10238-025-01587-1
J Biol Chem. 2025 Feb 13. pii: S0021-9258(25)00156-5. [Epub ahead of print] 108308

A CRISPR-edited isoform of the AMPK kinase LKB1 improves the response to cisplatin in A549 lung cancer cells.

Matheus Brandemarte Severino, Ana Paula Morelli, Isadora Carolina Betim Pavan, Mariana Camargo Silva Mancini, Mariana Marcela Góis, Rafael Junqueira Borges, Renata Rosseto Braga, Luiz Guilherme Salvino da Silva, Nathalia Quintero-Ruiz, Maíra Maftoum Costa, Wesley de Lima Oliveira, Rosângela Maria Neves Bezerra, Eduardo Rochete Ropelle, Fernando Moreira Simabuco.

  Lung cancer presents the highest mortality rate in the world when compared to other cancer types and often presents chemotherapy resistance to cisplatin. The A549 non-small cell lung cancer (NSCLC) line is widely used as a model for lung adenocarcinoma studies since it presents a high proliferative rate and a nonsense mutation in the STK11 gene. The LKB1 protein, encoded by the STK11 gene, is one of the major regulators of cellular metabolism through AMPK activation under nutrient deprivation. Mutation in the STK11 gene in A549 cells potentiates cancer hallmarks, such as deregulation of cellular metabolism, aside from the Warburg effect, mTOR activation, autophagy inhibition, and NRF2 and redox activation. In this study, we investigated the integration of these pathways associated with the metabolism regulation by LKB1/AMPK to improve cisplatin response in the A549 cell line. We first used the CRISPR/Cas9 system to generate cell lines with a CRISPR-edited LKB1 isoform (called Super LKB1), achieved through the introduction of a +1 adenine insertion in the first exon of the STK11 gene after NHEJ mediated repair. This insertion led to the expression of a higher molecular weight protein containing an alternative exon described in the Peutz-Jeghers Syndrome (PJS). Through metabolic regulation by Super LKB1 expression and AMPK activation, we found an increase in autophagy flux (LC3 GFP/RFP p<0.05), as well as a reduction in the phosphorylation of mTORC1 downstream targets (S6K2 phospho-Serine 423; p<0.05; and S6 ribosomal protein phospho-Serine 240/244; p<0.03). The NRF2 protein exhibited increased levels and more nuclear localization in A549 WT (wild-type) cells compared to the edited cells (p<0.01). We also observed lower levels of H2O2 in the WT A549 cells, as a possible result of NRF2 activation, and a higher requirement of cisplatin to achieve the IC50 (WT: 10 μM; c2SL+: 5.5 μM; c3SL+: 6 μM). The data presented here suggests that the regulation of molecular pathways by the novel Super LKB1 in A549 cells related to metabolism, mTORC1, and autophagy promotes a better response of lung cancer cells to cisplatin. This NHEJ-CRISPR-based approach may be potentially used for lung cancer gene therapy.

Keywords:  CRISPR/Cas9; STK11(LKB1); autophagy; cisplatin; metabolism; non-small cell lung cancer (NSCLC)

DOI:  https://doi.org/10.1016/j.jbc.2025.108308
Crit Rev Oncol Hematol. 2025 Feb 18. pii: S1040-8428(25)00057-5. [Epub ahead of print] 104669

Systemic Immune-Inflammation Index as a Predictor of Survival in Non-Small Cell Lung Cancer Patients Undergoing Immune Checkpoint Inhibition: A Systematic Review and Meta-Analysis.

Ye Zhang, Yeye Chen, Chao Guo, Shanqing Li, Cheng Huang.

   BACKGROUND: This meta-analysis aims to evaluate the association between pretreatment systemic immune-inflammation index (SII) levels and progression-free survival (PFS) and overall survival (OS) in NSCLC patients receiving immune checkpoint inhibitors (ICIs).
METHODS: A systematic search was conducted across PubMed, Embase, and Web of Science. Hazard ratios (HRs) with 95% confidence intervals (CIs) for PFS and OS were extracted or calculated. Random-effects models were employed to pool the results and subgroup analyses were performed based on study characteristics, treatment regimens, and analytical methods.
RESULTS: Two prospective and 11 retrospective studies involving 2,342 NSCLC patients treated with ICIs were included. A high pretreatment SII was significantly associated with poor PFS (HR: 2.05, 95% CI: 1.59-2.64, p < 0.001; I2 = 42%) and poor OS (HR: 1.54, 95% CI: 1.29-1.82, p < 0.001; I2 = 22%). Subgroup analyses according to the country of the study, lines of treatment, cancer stage, methods for determining the cutoffs of SII, and the analytic models showed consistent results (p for subgroup difference all > 0.05). Interestingly, the subgroup analyses indicated a stronger association in patients receiving ICIs alone versus those receiving concurrent chemotherapy (p for subgroup difference = 0.04).
CONCLUSIONS: High pretreatment SII is associated with worse PFS and OS in NSCLC patients treated with ICIs, particularly for the patients receiving ICIs alone without concurrent chemotherapy.

Keywords:  Immune checkpoint inhibitors; Meta-analysis; Non-small cell lung cancer; Survival; Systemic immune-inflammation index

DOI:  https://doi.org/10.1016/j.critrevonc.2025.104669
Sci Rep. 2025 Feb 17. 15(1): 5812

A method for the identification of lactate metabolism-related prognostic biomarkers and its validations in non-small cell lung cancer.

Weiyang Yang, Miao Gu, Yabin Zhang, Yunfan Zhang, Tao Liu, Di Wu, Juntao Deng, Min Liu, Youwei Zhang.

Lactate metabolism (LM) plays a crucial role in tumor progression and therapy resistance in non-small cell lung cancer (NSCLC). Several methods had been developed for NSCLC prognosis prediction based on lactate metabolism-related information. The existing methods for the construction of prognosis prediction models are mostly based on single models such as linear models, SVM, and decision trees. Prognosis biomarkers and prognosis prediction models based on this kind of methods often have limited prognostic performance. In this study, we proposed a novel methodology for constructing prognosis prediction model and identifying lactate-related prognostic biomarkers in NSCLC. We first screened for lactate metabolism-related malignant genes from the scRNA-Seq data of NSCLC malignant cells. We proposed a Cox elastic-net regression combined with genetic algorithm (GA-EnCox) to predict prognosis and optimize the selection of key biomarkers. We identified five key LM-related genes (LYPD3, KRT8, CCT6A, PSMB7, and HMGA1) that significantly correlated with patient prognosis in LUAD cohorts. The prognostic model constructed with these genes outperformed other currently popular models across multiple datasets, demonstrating stable predictive capability. Survival analysis based on bulk RNA-Seq data demonstrated that the low-risk group had significantly better overall survival compared to the high-risk group. Further analysis revealed that lactate metabolism-related prognosis risk might be associated with monocyte lineages such as macrophages and DC's infiltration and these prognosis biomarkers may indicate the therapeutic responses of immune checkpoint inhibitors for NSCLC patients. More importantly, we validated HMGA1 and KRT8 at protein level and their association with histologic grades, stages, and clinical outcomes in consistently treated in-house NSCLC cohorts. Finally, we experimentally validated one of the biomarkers, HMGA1, confirming its role in promoting malignant phenotypes of NSCLC. This study provides valuable insights into the role of lactate metabolism-related biomarkers and their impact on patient outcomes, it was expected to provide important reference value for prognosis assessment and personalized treatment decision of NSCLC patients.

DOI: https://doi.org/10.1038/s41598-025-85620-z
J Cachexia Sarcopenia Muscle. 2025 Feb;16(1): e13734

SIRT6 Ameliorates Cancer Cachexia-Associated Adipose Wasting by Suppressing TNFR2 Signalling in Mice.

Kang Xu, Yida Wang, Fang Wang, Yannan Guo, Yu Ren, Vivien Low, Sungyun Cho, Qingfei Liu, Ying Qiu, Xue Li, Kang Yu, Zhongchi Li, Zhao Wang.

   BACKGROUND: Cachexia is a wasting syndrome associated with imbalanced energy metabolism and loss of adipose and muscle tissues and contributes to morbidity and mortality in ageing as well as in patients with severe chronic diseases, including cancer. At present, there are no treatments addressing cachexia that have reached validation to be used in the clinic. In this study, we investigate the protective role of SIRT6, an important regulator of energy homeostasis and health preservation, against Lewis lung carcinoma (LLC)-induced cachexia.
METHODS: SIRT6 levels of serum from gastric cancer patients (n = 22, 65.27 ± 12.50 years old, 40.9% females) and healthy controls (n = 22, 63.50 ± 10.77 years old, 45.4% females) were measured to evaluate the correlation between circulating SIRT6 levels and cancer cachexia development. Ten-week-old SIRT6 transgenic (TG) and wild type (WT) male mice injected with LLC cells (1.5 × 106 per mouse) were used to investigate the protective effects of SIRT6 on cachexia-associated adipose browning and lipolysis and the underlying mechanisms. We explored the effect of SIRT6 on LLC-conditioned medium induced lipolysis in mature adipocytes, differentiated from primary mouse embryonic fibroblasts (MEFs). We evaluated the in vitro effect of a SIRT6 activator by treatment of MDL800.
RESULTS: SIRT6 concentrations were significantly higher in non-cachectic cancer patients (3.41 ± 0.30 ng/mL) compared to cachectic cancer patients (3.20 ± 0.23 ng/mL, p < 0.01), suggesting the negative correlation between SIRT6 level and cachexia in patients with cancer. SIRT6 overexpression significantly ameliorated tumour-induced wasting and energy expenditure in white adipose tissues (eWAT mass loss: 66% in WT vs. 32% in TG; iWAT mass loss: 69% in WT vs. 40% in TG) through suppression of browning and lipolysis. In LLC-induced cachexia, tumour necrosis factor-α receptor 2 (TNFR2) mediated the inhibition of SIRT6 on lipolytic signalling, because the difference in lipolysis between the WT and SIRT6 knockout group was almost eliminated by TNFR2 neutralizing antibody. Increased serum TNFR2 concentration was found in cachectic cancer patients (690.41 pg/mL in non-cachectic vs. 1166.98 pg/mL in cachectic patients, p < 0.05). A selective SIRT6 pharmaceutical activator, MDL800, could completely reverse LLC-induced lipolysis in adipocytes.
CONCLUSION: We found an unexpected beneficial function of SIRT6 in cancer cachexia, demonstrating that increased SIRT6 expression or activity is capable of protecting the host against cachexia-associated tissue wasting, providing a concept of future therapies for cachexia.

Keywords:  SIRT6; SIRT6 activator; TNFR2 antagonist; adipose wasting; cachexia

DOI:  https://doi.org/10.1002/jcsm.13734
Cureus. 2025 Jan;17(1): e77795

Significance of Neutrophil-to-Lymphocyte Ratio in Predicting the Efficacy of Anamorelin for Cancer Cachexia.

Yusuke Nakazawa, Kanako Watanabe, Ako Gannichida, Tadashi Uwagawa, Takashi Kawakubo.

  Introduction Cancer cachexia is a multifactorial syndrome characterized by persistent skeletal muscle loss and poor prognosis in cancer patients. Anamorelin, a ghrelin receptor agonist, may alleviate cachexia symptoms by increasing appetite and promoting weight gain, though its clinical efficacy remains insufficiently explored. Given the involvement of cancer-inducing cytokines in cachexia, the neutrophil-to-lymphocyte ratio (NLR), an inflammatory biomarker, may serve as a predictor of therapeutic outcomes in this condition. This study aimed to evaluate the role of NLR in assessing the therapeutic effects of anamorelin and its prognostic value in patients with cancer cachexia. Methods This study included patients with cancer cachexia associated with pancreatic, non-small cell lung, gastric, or colorectal cancer who received anamorelin between April 2021 and December 2023. Patients were categorized based on their NLR (<5 or ≥5) at four weeks post-anamorelin administration. Changes in NLR and one-year overall survival (OS) rates were compared between groups. Baseline NLR was also assessed for its impact on survival outcomes. Statistical analyses included the Kaplan-Meier method for survival analysis, and receiver operating characteristic (ROC) analysis was used to determine the optimal baseline NLR cutoff for achieving a posttreatment NLR < 5. Results Of the 66 patients who received anamorelin, 42 had pancreatic cancer, 14 had non-small cell lung cancer, 6 had gastric cancer, and 4 had colorectal cancer. Patients were stratified into two groups based on their NLR at four weeks: NLR < 5 (n = 50, 76%) and NLR ≥ 5 (n = 16, 24%). In the NLR < 5 group, the mean NLR decreased significantly from 3.71 to 2.44, while in the NLR ≥ 5 group, it increased from 5.70 to 9.52. The one-year OS was significantly higher in the NLR < 5 group (62%, n = 31/50) compared to the NLR ≥ 5 group (33%, n = 5/16). Baseline NLR classification, however, showed no significant survival difference between the baseline NLR < 5 group (58%, n = 21/51) and the NLR ≥ 5 group (41%, n = 6/15). ROC analysis identified a baseline NLR < 4.4 as predictive of achieving a posttreatment NLR < 5 (AUC, 0.78; sensitivity, 80%; specificity, 75%), with significantly higher one-year OS observed in the baseline NLR < 4.4 group (68%, n = 29/42) compared to the NLR ≥ 4.4 group (34%, n = 8/24). Conclusions These findings highlight the potential of NLR as a prognostic marker and suggest that initiating anamorelin treatment with a baseline NLR < 4.4 is likely to improve outcomes, emphasizing the importance of NLR-based therapeutic interventions.

Keywords:  anamorelin; cancer cachexia; efficacy prediction; neutrophil-to-lymphocyte ratio; prognostic biomarker

DOI:  https://doi.org/10.7759/cureus.77795
Sci Rep. 2025 Feb 17. 15(1): 5729

STK11 genetic alterations in metastatic EGFR mutant lung cancer.

Dandan Yin, Xiyi Lu, Xiao Liang, Yiting Lu, Lei Xiong, Pingping Wu, Tingting Wang, Jinfei Chen.

  This study was conducted to investigate the relationship between STK11 genetic alterations and the outcomes of patients with metastatic EGFR mutant lung cancer. Clinical characteristics and genomic data were downloaded from the cBioPortal database. The information of the case with STK11 mutation was collected from Jiangyin People's Hospital. Univariate and multivariate analyses were performed to distinguish the prognostic differences. Outcomes were analyzed before and after propensity score matching (PSM). A patient with STK11 mutation was insensitive to osimertinib and had an extremely poor prognosis. Further analysis showed that STK11 mutations had a strong mutual exclusion with EGFR mutations. A total of 960 patients with metastatic EGFR mutant lung adenocarcinoma were enrolled in the prognostic analysis. STK11 alternation was a significant predictor of worse outcomes in univariate or multivariate analyses. After PSM, patients with STK11 alternations still exhibited poor prognoses. Cell culture experiments also showed that the loss of STK11 could contribute to the resistance of osimertinib. Functionally, STK11 mutation was positively associated with metabolic signaling pathways and immune infiltrates negatively. Through drug screening, trametinib was identified to sensitize osimertinib in the STK11-deficient cell. This study found that STK11 genetic alterations portend a worse prognosis for patients with metastatic EGFR mutant lung cancer and led to osimertinib resistance potentially. MEK inhibitors could sensitize osimertinib in the STK11-deficient cell.

Keywords:  EGFR; Lung cancer; Osimertinib; Prognosis; STK11

DOI:  https://doi.org/10.1038/s41598-024-74779-6
J Thorac Dis. 2025 Jan 24. 17(1): 93-108

PLCXD3-ALK, a novel ALK rearrangement in lung squamous cell carcinoma and its clinical responses to ALK inhibitors.

Kaidi Chen, Xiuqiong Chen, Xinyue Wang, Bing Yan, Aiqin Liu, Youhui Wang, Jing Zhou, Qianhui Wei, Yi Pan, Richeng Jiang.

   Background: Lung cancer is the leading cause of cancer-related death worldwide, of which anaplastic lymphoma kinase fusion positive (ALK +) non-small cell lung cancer (NSCLC) accounts for 3-7. Here, we identified a new fusion gene PLCXD3-ALK (P1, A19) from a patient with advanced lung squamous cell carcinoma (LUSC) by next-generation sequencing (NGS). We aimed to evaluate its oncogenic potential by performing functional studies in vitro and tumorigenicity in vivo of this fusion protein.
Methods: We performed functional experiments in NIH-3T3 cells with stable expression of PLCXD3-ALK including soft agar colony formation assay, cell proliferation and viability assays, and transwell assay. The activation of downstream pathways and the response to ALK inhibitors crizotinib and alectinib were demonstrated by western blotting (WB). In addition, we further evaluated the tumorigenicity of the PLCXD3-ALK mutants in nude mice.
Results: Similar to EML4-ALK, the PLCXD3-ALK fusion promoted proliferation and the capacity for non-anchorage-dependent growth of NIH-3T3 cells. We demonstrated that PLCXD3-ALK can activate ALK self-phosphorylation and downstream pathways, which could be inhibited by the addition of ALK inhibitors. Moreover, we observed that this gene could provoke oncogenic transformation in nude mice. Meanwhile, the patient was monitored for disease progression with computed tomography (CT) scanning during treatment with alectinib, and a benefit was observed.
Conclusions: We identified and functionally validated PLCXD3-ALK as a novel rare fusion in NSCLC that has not been previously reported. It can serve as a meaningful therapeutic target for ALK inhibitors of ALK + NSCLC.

Keywords:  Non-small cell lung cancer (NSCLC); PLCXD3-ALK fusion; anaplastic lymphoma kinase inhibitors (ALK inhibitors); targeted therapy

DOI:  https://doi.org/10.21037/jtd-24-1428