bims-meluca Biomed News
on Metabolism of non-small cell lung carcinoma
Issue of 2021‒02‒14
eleven papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge


  1. Transl Lung Cancer Res. 2021 Jan;10(1): 304-313
    Kocher F, Amann A, Zimmer K, Geisler S, Fuchs D, Pichler R, Wolf D, Kurz K, Seeber A, Pircher A.
      Background: Metabolic profiling in non-small cell lung cancer (NSCLC) may identify key metabolic vulnerabilities and shows enormous discovery potential. Preclinical studies showed that metabolic rewiring in cancer plays an essential role in modulation of immunotherapy response. However, this situation is understudied in the clinical setting. Therefore, we aimed to evaluate the plasma metabolic profile of immune checkpoint inhibitor (CI) responding versus non-responding NSCLC patients. The aim of this project is to identify potential predictive biomarkers for CI response.Methods: Plasma samples from CI treated NSCLC patients were analysed at baseline and at the first follow up scan by using a broad targeted metabolomics mass spectrometry panel, and were compared to healthy controls. For further validation of identified key alterations high-performance liquid chromatography (HPLC) for tryptophan (Trp) and kynurenine (Kyn) as indicator of IDO-activity was performed.
    Results: Sixty-seven metabolites were significantly altered in NSCLC patients compared to healthy controls. The metabolic profile of patients with primary CI resistance showed an increase in indoleamine-2,3-dioxygenase (IDO) and a decrease in branched-chain amino acids (BCAA) compared to baseline concentrations. Deregulated IDO activity was validated by additional HPLC measurements, which revealed that baseline Trp levels were predictive for CI response. According to receiver operating characteristic (ROC)-analysis baseline Trp levels ≥49.3 µmol/L predicted disease control at the first follow up scan with a sensitivity of 89% and a specificity of 71%.
    Conclusions: We showed that NSCLC patients are characterized by a distinct metabolic profile compared to healthy controls. Moreover, metabolic changes during CI therapy were observed. Of those IDO metabolism seemed to play an important role in primary CI resistance. Trp as a surrogate parameter of IDO activity is a promising biomarker in patients undergoing treatment with CIs and might be a future marker in trials investigating IDO inhibitors.
    Keywords:  Checkpoint inhibitor (CI); indoleamine-2,3-dioxygenase (IDO); metabolic profile; non-small cell lung cancer (NSCLC); tryptophan (Trp)
    DOI:  https://doi.org/10.21037/tlcr-20-380
  2. BMJ Support Palliat Care. 2021 Feb 09. pii: bmjspcare-2020-002838. [Epub ahead of print]
    Phillips I, Allan L, Hug A, Westran N, Heinemann C, Hewish M, Mehta A, Saxby H, Ezhil V.
      INTRODUCTION: European Society for Clinical Nutrition and Metabolism guidelines recommend that patients with cancer should be screened for malnutrition at diagnosis. The dietetic assessment and intervention in lung cancer study investigated the nutritional status of patients with non-small cell lung cancer (NSCLC) and the need for dietetic intervention.METHODS: In this observational cohort pilot study, patients with stage 3b and 4 NSCLC were assessed prior to starting first line systemic anticancer therapy (SACT) with a range of measurements and questionnaires. We report the outcomes related to the Patient Generated Subjective Global Assessment tool (PG-SGA), RESULTS: 96 patients were consented between April 2017 and August 2019. The PG-SGA identified that 78% of patients required specialist nutritional advice; with 52% patients having a critical need for dietetic input and symptom management. Results were dominated by symptom scores. As a screening test, one or more symptoms or recent weight loss history had a sensitivity of 88% (95% CI 78.44% to 94.36%) and specificity of 95.24% (95% CI 76.18% to 99.88%) for need for dietetic intervention.
    CONCLUSION: A large proportion of patients with NSCLC have a high symptom burden and are at risk of malnutrition prior to starting SACT and would benefit from dietetic review. It is imperative that oncologists and healthcare professionals discuss weight loss history and symptoms with lung cancer patients to correct nutritional deficiencies and resolve symptoms prior to starting treatment.
    Keywords:  anorexia; cachexia; lung; quality of life; supportive care
    DOI:  https://doi.org/10.1136/bmjspcare-2020-002838
  3. Transl Lung Cancer Res. 2021 Jan;10(1): 128-142
    Luo Y, Yang Y, Peng P, Zhan J, Wang Z, Zhu Z, Zhang Z, Liu L, Fang W, Zhang L.
      Background: Acquired resistance is a challenge for epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer. Here, we propose a novel treatment strategy based on recent lipid metabolism work.Methods: We applied a variety of experimental methods such as immunoblotting, MTT, si-RNA, and animal models, to demonstrate the relationship between EGFR and low-density lipoprotein receptor (LDLR) and the effects of statin monotherapy, and TKI monotherapy, and their combination on cell proliferation at the cell level and animal level.
    Results: LDLR has a positive correlation with EGFR, EGFR signaling upregulates LDLR expression through the SREBP-1 dependent pathway, EGFR mutation cells count on lipids to survive and grow. Combined with a molecule-targeted drug, atorvastatin not only enhances the treatment effect in vitro, but also mitigates the growth of NSCLC in vivo. In this animal experiment, the combination medicine (atorvastatin with TKI) has a better tumor suppression effect on NSCLC. In HCC827 cell line, the average tumor shrinkage is about 68% in Gefitinib group, and about 49% in atorvastatin group, but about 89% in combination group. In H1975 cell line, the average tumor shrinkage is about 18% in Osimertinib group, and about 8% in atorvastatin group, but about 44% in combination group.
    Conclusions: the combination of an EGFR-TKI and a statin for EGFR mutant NSCLC may be a novel tumor inhibiting treatment.
    Keywords:  Non-small cell lung cancer (NSCLC); cholesterol; epidermal growth factor receptor (EGFR); low-density lipoprotein receptor (LDLR); metabolic therapy
    DOI:  https://doi.org/10.21037/tlcr-20-812
  4. Anticancer Agents Med Chem. 2021 Feb 11.
    Bilgin E, Atli G, Duman BB, Okten AI.
      BACKGROUND: Oxidative stress lead to an imbalanced prooxidant/antioxidant status can be a critical factor affecting the lung cancer etiopathology. The antioxidant system provides primary protection under oxidative stress.OBJECTIVE: The purpose of the study was to investigate the serum antioxidant system status in brain metastatic and non-metastatic lung cancer patients with different cell types.
    METHODS: In this prospective study, 33 patients with lung cancer metastasis (metastatic patient group), 36 lung cancer patients (non-metastatic patient group) and 25 healthy control groups were included. Enzymatic (superoxide dismutase, SOD; glutathione peroxidase, GPX; and glutathione reductase, GR) and non-enzymatic (glutathione, GSH) antioxidant system biomarkers with thiobarbituric acid reactive substances (TBARS) levels were studied in the serum samples of the control and patient groups. The oxidative stress biomarkers were measured spectrophotometrically.
    RESULTS: SOD activity increased though TBARS levels and GR activity decreased in both patient groups compared to the control. GPX activity increased only in the non-metastatic group. Antioxidant biomarkers varied between small cell and non-small cell group patients. GR activity and GSH levels were significantly higher in the non-metastatic group compared to the metastatic group. There were also found correlations between antioxidant parameters in the non-metastatic group.
    CONCLUSIONS: It was emphasized the imbalanced antioxidant system in the duration of the disease related to not only cell type and also the metastatic structure. This is the preliminary study exhibiting the contribution of antioxidant imbalance in different subtypes with varied prognosis and behavior of lung cancer in the presence of brain metastasis. Therefore, oxidative stress biomarkers can serve as a useful tool to get information about the progression of lung cancer. Thus it may provide fundamental data for further cancer researches when considering the diagnosis of the disease.
    Keywords:  Antioxidant system; NSCLC; brain; lung cancer; metastasis; serum
    DOI:  https://doi.org/10.2174/1871520621666210211163055
  5. J Proteomics. 2021 Feb 06. pii: S1874-3919(21)00021-X. [Epub ahead of print] 104122
    Han X, Chen L, Hu Z, Chen L, Sun P, Wang Y, Liu Y.
      Pemetrexed (PEM), a multi-target folate antagonist, has been extensively used for the treatment of non-small cell lung cancer (NSCLC). However, the therapeutic efficacy of PEM is limited by tumor resistance. In this project, iTRAQ and parallel reaction monitoring (PRM)-based LC-MS/MS comparative proteomic analysis was performed to identify protein determinants of PEM resistance in A549/PEM cells versus A549 parental cells. A total of 567 differentially expressed proteins (DEPs) were identified by iTRAQ analysis. The function and classification of DEPs were analyzed through GO and KEGG Pathway databases. Moreover, PRM analysis further validated the expression changes of 14 DEPs identified by iTRAQ analysis. Moreover, insulin-like growth factor (IGF) 2 mRNA-binding protein 2 (IGF2BP2) or folate receptor alpha (FOLR1) knockdown weakened PEM resistance, reduced cell viability and promoted cell apoptosis in A549/PEM cells. IGF2BP2 depletion inhibited cell migration, invasion and epithelial-mesenchymal transition (EMT), while FOLR1 loss had no much effect on cell migration, invasion and EMT in A549/PEM cells. Our study can provide a deep insight into molecular mechanisms of PEM resistance in NSCLC and contribute to the development of more effective therapeutic schedules. SIGNIFICANCE: Our study can provide deeper insight into molecular mechanisms of PEM resistance in NSCLC and contribute to the development of more effective therapeutic schedules.
    Keywords:  Non-small cell lung cancer; Parallel reaction monitoring; Pemetrexed; Resistance; iTRAQ
    DOI:  https://doi.org/10.1016/j.jprot.2021.104122
  6. Ann Palliat Med. 2021 Feb 07. pii: apm-20-2328. [Epub ahead of print]
    Zhang C, Li XK, Cong ZZ, Zheng C, Luo C, Xie K, Xu Y, Gu WF, Qiang Y, Shen Y.
      BACKGROUND: Nowadays, controlling nutritional status (CONUT) has been used as a prognostic factor in variety of cancers. However, no consensus has been reached on the prognostic value of CONUT in lung cancer. In this study, we aim to investigate the role of CONUT in survival of patients with lung cancer.METHODS: EMBASE, web of science, and Medline were used to search articles in English-language journals. The association between CONUT score and survival of patients with lung cancer was evaluated by using pooled HRs and their 95% CIs. Chi-square test and I-Square was used to test heterogeneity among studies. Analyses were all performed using Stata 13.0 (Stata Corporation, College Station, TX).
    RESULTS: Eight studies with 1,836 patients were eventually included in this meta-analysis. The pooled results showed that high CONUT score had an unfavorable impact on OS (HR =1.63, 95% CI: 1.30-2.04), DFS (HR =1.75, 95% CI: 1.35-2.26), CSS (HR =1.45, 95% CI: 1.01-2.07) and PFS (HR =1.67, 95% CI: 0.99-2.35), compared with those with low-CONUT.
    CONCLUSIONS: CONUT can be used as a predictor of prognosis in patients with lung cancer. HighCONUT score was significantly associated with poor OS, DFS, CSS and PFS.
    Keywords:  Controlling nutritional status (CONUT); lung cancer; prognostic factor
    DOI:  https://doi.org/10.21037/apm-20-2328
  7. Front Oncol. 2020 ;10 571384
    Xiao D, He J, Guo Z, He H, Yang S, Huang L, Pan H, He J.
      Introduction: RHPN2, a member of rhophilin family of rho-binding proteins, regulates actin cytoskeleton and vesicular trafficking, and promotes mesenchymal transformation in cancer. We have found that RHPN2 was significantly mutated in lung adenocarcinoma (LUAD). However, the role of RHPN2 in lung cancer is not fully understood.Methods: In the present study, we investigated the expression of RHPN2 in 125 patients with LUAD by qRT-PCR and correlated its expression with clinical characteristics. The effects of RHPN2 on the proliferation and invasion of lung cancer cells were determined by CCK-8 and in vitro transwell assays, clonogenic assay, and xenograft mouse model. The RhoA pull down assay and Western blotting were performed to elucidate the mechanism of RNPN2 in tumorigenesis of lung cancer.
    Results: RHPN2 was overexpressed in tumors from LUAD, and high levels of RHPN2 were associated with poor prognosis of LUAD patients. RHPN2 was required for proliferation and invasion of lung cancer cells. Intriguingly, overexpression of RHPN2 conferred the resistance to glutamine depletion in lung cancer cells. Mechanistic studies revealed that ectopic overexpression of RHPN2 promoted the stability of c-Myc protein via phosphorylation at Ser62 and increased c-Myc target glutamine synthetase (GS). Analysis of GS expression in clinical sample showed that the expression of GS was elevated in tumor cells. Kaplan-Meier analysis revealed that high levels of GS were significantly associated with worse overall survival time of the patients with LUAD.
    Conclusions: Taken together, this study suggested that RHPN2 was involved in tumorigenesis of lung cancer via modulating c-Myc stability and the expression of its target GS in lung adenocarcinoma, which links RHPN2 and glutamine metabolism.
    Keywords:  RHPN2; c-Myc protein; glutamine synthetase; lung adenocarcinoma; tumorigenesis
    DOI:  https://doi.org/10.3389/fonc.2020.571384
  8. Diagnostics (Basel). 2021 Jan 29. pii: 196. [Epub ahead of print]11(2):
    Mograbi B, Heeke S, Hofman P.
      Despite the recent implementation of immunotherapy as a single treatment or in combination with chemotherapy for first-line treatment of advanced non-small cell lung cancer (NSCLC), many patients do not benefit from this regimen due to primary treatment resistance or toxicity. Consequently, there is an urgent need to develop efficient biomarkers that can select patients who will benefit from immunotherapy thereby providing the appropriate treatment and avoiding toxicity. One of the biomarkers recently described for the stratification of NSCLC patients undergoing immunotherapy are mutations in STK11/LKB1, which are often associated with a lack of response to immunotherapy in some patients. Therefore, the purpose of this review is to describe the different cellular mechanisms associated with STK11/LKB1 mutations, which may explain the lack of response to immunotherapy. Moreover the review addresses the co-occurrence of additional mutations that may influence the response to immunotherapy and the current clinical studies that have further explored STK11/LKB1 as a predictive biomarker. Additionally this work includes the opportunities and limitations to look for the STK11/LKB1 status in the therapeutic strategy for NSCLC patients.
    Keywords:  KRAS; STK11/LKB1; biomarker; immunotherapy; non-small cell lung carcinoma; targeted therapy
    DOI:  https://doi.org/10.3390/diagnostics11020196
  9. Surg Today. 2021 Feb 09.
    Miura A, Yamamoto H, Sato H, Tomioka Y, Shiotani T, Suzawa K, Miyoshi K, Otani S, Okazaki M, Sugimoto S, Yamane M, Toyooka S.
      PURPOSE: The number of elderly patients who undergo surgery is increasing, even though they are at a high risk due to a decreased physical strength. Furthermore, sarcopenia is generally associated with a poor prognosis in patients with non-small cell lung cancer (NSCLC).METHODS: This study included NSCLC patients  ≥ 65 years old who underwent pulmonary resection in our hospital between 2012 and 2015. Sarcopenia was assessed using the psoas muscle mass index based on computed tomography at the level of the third lumbar vertebra. We elucidated the impact of sarcopenia on short- and long-term outcomes after surgery.
    RESULTS: We enrolled 259 patients, including 179 with sarcopenia. Patients with sarcopenia before surgery tended to have postoperative complications (p = 0.0521), although they did not show a poor prognosis. In patients with sarcopenia, a multivariate analysis revealed that postoperative complications and the progression of sarcopenia 1 year after surgery were significant risk factors for a poor prognosis (p = 0.0169 and 0.00370, respectively).
    CONCLUSIONS: The progression of sarcopenia after surgery is associated with a poor prognosis in elderly NSCLC patients with sarcopenia. A strategy to prevent postoperative progressive sarcopenia may be necessary for improving the clinical outcome of this population.
    Keywords:  Elderly patient; Non-small cell lung cancer; Pulmonary resection; Sarcopenia
    DOI:  https://doi.org/10.1007/s00595-020-02221-1
  10. Cancers (Basel). 2021 Feb 10. pii: 739. [Epub ahead of print]13(4):
    Kim D, Kim Y, Lee BB, Cho EY, Han J, Shim YM, Kim DH.
      This study aimed at understanding the effect of metformin on histone H3 methylation, DNA methylation, and chromatin accessibility in lung cancer cells. Metformin significantly reduced H3K4me3 level at the promoters of positive cell cycle regulatory genes such as CCNB2, CDK1, CDK6, and E2F8. Eighty-eight genes involved in cell cycle showed reduced H3K4me3 levels in response to metformin, and 27% of them showed mRNA downregulation. Metformin suppressed the expression of H3K4 methyltransferases MLL1, MLL2, and WDR82. The siRNA-mediated knockdown of MLL2 significantly downregulated global H3K4me3 level and inhibited lung cancer cell proliferation. MLL2 overexpression was found in 14 (33%) of 42 NSCLC patients, and a Cox proportional hazards analysis showed that recurrence-free survival of lung adenocarcinoma patients with MLL2 overexpression was approximately 1.32 (95% CI = 1.08-4.72; p = 0.02) times poorer than in those without it. Metformin showed little effect on DNA methylation and chromatin accessibility at the promoter regions of cell cycle regulatory genes. The present study suggests that metformin reduces H3K4me3 levels at the promoters of positive cell cycle regulatory genes through MLL2 downregulation in lung cancer cells. Additionally, MLL2 may be a potential therapeutic target for reducing the recurrence of lung adenocarcinoma.
    Keywords:  H3K4 methylation; MLL2; cell cycle; lung cancer; metformin
    DOI:  https://doi.org/10.3390/cancers13040739
  11. Cancers (Basel). 2021 Jan 29. pii: 508. [Epub ahead of print]13(3):
    Di Gregorio E, Miolo G, Saorin A, Muraro E, Cangemi M, Revelant A, Minatel E, Trovò M, Steffan A, Corona G.
      Radical hemithoracic radiotherapy (RHRT) represents an advanced therapeutic option able to improve overall survival of malignant pleural mesothelioma patients. This study aims to investigate the systemic effects of this radiotherapy modality on the serum metabolome and their potential implications in determining the individual clinical outcome. Nineteen patients undergoing RHRT at the dose of 50 Gy in 25 fractions were enrolled. Serum targeted metabolomics profiles were investigated at baseline and the end of radiotherapy by liquid chromatography and tandem mass spectrometry. Univariate and multivariate OPLS-DA analyses were applied to study the serum metabolomics changes induced by RHRT while PLS regression analysis to evaluate the association between such changes and overall survival. RHRT was found to affect almost all investigated metabolites classes, in particular, the amino acids citrulline and taurine, the C14, C18:1 and C18:2 acyl-carnitines as well as the unsaturated long chain phosphatidylcholines PC ae 42:5, PC ae 44:5 and PC ae 44:6 were significantly decreased. The enrichment analysis showed arginine metabolism and the polyamine biosynthesis as the most perturbed pathways. Moreover, specific metabolic changes encompassing the amino acids and acyl-carnitines resulted in association with the clinical outcome accounting for about 60% of the interpatients overall survival variability. This study highlighted that RHRT can induce profound systemic metabolic effects some of which may have a significant prognostic value. The integration of metabolomics in the clinical assessment of the malignant pleural mesothelioma could be useful to better identify the patients who can achieve the best benefit from the RHRT treatment.
    Keywords:  biomarkers; cancers; mesothelioma; metabolomics; radiotherapy
    DOI:  https://doi.org/10.3390/cancers13030508