bims-meluca 2023-01-15 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2023–01–15
ten papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Clinical features and lipid metabolism genes as potential biomarkers in advanced lung cancer.
Battles against aberrant KEAP1-NRF2 signaling in lung cancer: intertwined metabolic and immune networks.
Overweight and Obesity are Associated with Poorer Survival Among Patients with Advanced Non-Small Cell Lung Cancer Receiving Platinum-Based Chemotherapy.
Intrinsic and Extrinsic Transcriptional Profiles That Affect the Clinical Response to PD-1 Inhibitors in Patients with Non-Small Cell Lung Cancer.
Landscape and clinical impact of metabolic alterations in non-squamous non-small cell lung cancer.
Impact of Type 2 Diabetes Mellitus on the Prognosis of Non-Small Cell Lung Cancer.
Neutrophil-to-Lymphocyte Ratio Is a Major Prognostic Factor in Non-small Cell Lung Carcinoma Patients Undergoing First Line Immunotherapy With Pembrolizumab.
Tumor-intrinsic IRE1α signaling controls protective immunity in lung cancer.
Large-scale clinico-genomic profile of non-small cell lung cancer with KRAS G12C: Results from LC-SCRUM-Asia study.
Lower SLC7A2 expression is associated with enhanced multidrug resistance, less immune infiltrates and worse prognosis of NSCLC.

BMC Cancer. 2023 Jan 09. 23(1): 36

Clinical features and lipid metabolism genes as potential biomarkers in advanced lung cancer.

María Merino Salvador, Lara Paula Fernández, Juan Moreno-Rubio, Gonzalo Colmenarejo, Enrique Casado, Ana Ramírez de Molina, María Sereno.

   BACKGROUND: Lung cancer is one of the most lethal tumors with a poor survival rate even in those patients receiving new therapies. Metabolism is considered one of the hallmarks in carcinogenesis and lipid metabolism is emerging as a significant contributor to tumor metabolic reprogramming. We previously described a profile of some lipid metabolism related genes with potential prognostic value in advanced lung cancer.
AIM: To analyze clinical and pathological characteristics related to a specific metabolic lipid genomic signature from patients with advanced lung cancer and to define differential outcome.
METHODS: Ninety samples from NSCLC (non-small cell lung cancer) and 61 from SCLC (small cell lung cancer) patients were obtained. We performed a survival analysis based on lipid metabolic genes expression and clinical characteristics. The primary end point of the study was the correlation between gene expression, clinical characteristics and survival.
RESULTS: Clinical variables associated with overall survival (OS) in NSCLC patients were clinical stage, adenocarcinoma histology, Eastern Cooperative Oncology Group (ECOG), number and site of metastasis, plasma albumin levels and first-line treatment with platinum. As for SCLC patients, clinical variables that impacted OS were ECOG, number of metastasis locations, second-line treatment administration and Diabetes Mellitus (DM). None of them was associated with gene expression, indicating that alterations in lipid metabolism are independent molecular variables providing complementary information of lung cancer patient outcome.
CONCLUSIONS: Specific clinical features as well as the expression of lipid metabolism-related genes might be potential biomarkers with differential outcomes.

Keywords:  Advanced stages; Lipid metabolism; Lung cancer; Overall survival

DOI:  https://doi.org/10.1186/s12885-023-10509-x
Theranostics. 2023 ;13(2): 704-723

Battles against aberrant KEAP1-NRF2 signaling in lung cancer: intertwined metabolic and immune networks.

Ke Xu, Jie Ma, Sean R R Hall, Ren-Wang Peng, Haitang Yang, Feng Yao.

  The Kelch-like ECH-associated protein 1/nuclear factor erythroid-derived 2-like 2 (KEAP1/NRF2) pathway is well recognized as a key regulator of redox homeostasis, protecting cells from oxidative stress and xenobiotics under physiological circumstances. Cancer cells often hijack this pathway during initiation and progression, with aberrant KEAP1-NRF2 activity predominantly observed in non-small cell lung cancer (NSCLC), suggesting that cell/tissue-of-origin is likely to influence the genetic selection during malignant transformation. Hyperactivation of NRF2 confers a multi-faceted role, and recently, increasing evidence shows that a close interplay between metabolic reprogramming and tumor immunity remodelling contributes to its aggressiveness, treatment resistance (radio-/chemo-/immune-therapy) and susceptibility to metastases. Here, we discuss in detail the special metabolic and immune fitness enabled by KEAP1-NRF2 aberration in NSCLC. Furthermore, we summarize the similarities and differences in the dysregulated KEAP1-NRF2 pathway between two major histo-subtypes of NSCLC, provide mechanistic insights on the poor response to immunotherapy despite their high immunogenicity, and outline evolving strategies to treat this recalcitrant cancer subset. Finally, we integrate bioinformatic analysis of publicly available datasets to illustrate the new partners/effectors in NRF2-addicted cancer cells, which may provide new insights into context-directed treatment.

Keywords:  KEAP1-NRF2 signaling; bioinformatics; metabolic reprogramming; non-small cell lung cancer; therapeutic vulnerabilities; tumor immune microenvironment

DOI:  https://doi.org/10.7150/thno.80184
Int J Gen Med. 2023 ;16 85-93

Overweight and Obesity are Associated with Poorer Survival Among Patients with Advanced Non-Small Cell Lung Cancer Receiving Platinum-Based Chemotherapy.

Noorwati Sutandyo, Arif Riswahyudi Hanafi, Achmad Mulawarman Jayusman, Sri Agustini Kurniawati, Muhamad Alfin Hanif.

   Background and Aim: Most patients with non-small cell lung cancer (NSCLC) are diagnosed in advanced-stage disease and therefore have poor overall survival. It remains unclear whether nutritional status affects response rate and overall survival in NSCLC patients. This study aimed to evaluate the association of nutritional status with treatment response and overall survival in patients with advanced stage of NSCLC.
Methods: Patients aged ≥18 years with stage II-IV NSCLC (January-June 2018) in a national cancer center in Indonesia were enrolled in this study. The patients were followed up for 2 years since NSCLC diagnosis was established. Clinical data including age, sex, histology of cancer, disease stage, cachexia, and weight status before chemotherapy were reviewed and analyzed. Logistic regression and Cox regression analyses were performed.
Results: A total of 174 patients (71% males, mean age = 58±9.4 years) was included. Complete response was found in <1% patients, partial response 41%, stable disease 33%, and progressive disease 25%. Median survival was 12 months (95% CI: 11-13 months). Mortality rate was 5.7 per 100 person-months. Poor survival was associated with being males (HR: 1.77, 95% CI: 1.15-2.72, P = 0.009), and overweight or obesity (HR 1.67, 95% CI: 1.04-2.69, P = 0.034). These associations were independent of sex, age, staging, histopathology, performance status and D-dimer level at baseline. Cachexia and BMI at baseline were not associated with treatment response.
Conclusion: Males and having overweight or obesity are independently associated with lower survival in patients with advanced stage of NSCLC undergoing platinum-based chemotherapy.

Keywords:  body mass index; lung cancer; nutritional status

DOI:  https://doi.org/10.2147/IJGM.S382577
Cancers (Basel). 2022 Dec 29. pii: 197. [Epub ahead of print]15(1):

Intrinsic and Extrinsic Transcriptional Profiles That Affect the Clinical Response to PD-1 Inhibitors in Patients with Non-Small Cell Lung Cancer.

Hye Eun Byeon, Seokjin Haam, Jae Ho Han, Hyun Woo Lee, Young Wha Koh.

  Using a machine learning method, we investigated the intrinsic and extrinsic transcriptional profiles that affect the clinical response to PD-1 inhibitors in 57 patients with non-small cell lung cancer (NSCLC). Among the top 100 genes associated with the responsiveness to PD-1 inhibitors, the proportion of intrinsic genes in lung adenocarcinoma (LUAD) (69%) was higher than in NSCLC overall (36%) and lung squamous cell carcinoma (LUSC) (33%). The intrinsic gene signature of LUAD (mean area under the ROC curve (AUC) = 0.957 and mean accuracy = 0.9) had higher predictive power than either the intrinsic gene signature of NSCLC or LUSC or the extrinsic gene signature of NSCLC, LUAD, or LUSC. The high intrinsic gene signature group had a high overall survival rate in LUAD (p = 0.034). When we performed a pathway enrichment analysis, the cell cycle and cellular senescence pathways were related to the upregulation of intrinsic genes in LUAD. The intrinsic signature of LUAD also showed a positive correlation with other immune checkpoint targets, including CD274, LAG3, and PDCD1LG2 (Spearman correlation coefficient > 0.25). PD-1 inhibitor-related intrinsic gene patterns differed significantly between LUAD and LUSC and may be a particularly useful biomarker in LUAD.

Keywords:  PD-1; PD-1/PD-L1-targeted therapy; PD-L1; biomarkers; gene expression profile; immunotherapy; machine learning; non-small cell lung cancer; tumor-intrinsic role

DOI:  https://doi.org/10.3390/cancers15010197
Transl Lung Cancer Res. 2022 Dec;11(12): 2464-2476

Landscape and clinical impact of metabolic alterations in non-squamous non-small cell lung cancer.

Anna V Ivanina Foureau, Wei Sha, David M Foureau, James T Symanowski, Carol J Farhangfar, Kathryn F Mileham.

   Background: Metabolomics studies to date have described widespread metabolic reprogramming events during the development of non-squamous non-small cell lung cancer (NSCLC). Extending far beyond the Warburg effect, not only is carbohydrate metabolism affected, but also metabolism of amino acids, cofactors, lipids, and nucleotides.
Methods: We evaluated the clinical impact of metabolic reprogramming. We performed comparative analysis of publicly available data on non-squamous NSCLC, to identify concensus altered metabolic pathways. We investigated whether alterations of metabolic genes controlling those consensus metabolic pathways impacted clinical outcome. Using the clinically annotated lung adenocarcinoma (LUAD) cohort from The Cancer Genome Atlas, we surveyed the distribution and frequency of function-altering mutations in metabolic genes and their impact on overall survival (OS).
Results: We identified 42 metabolic genes of clinical significance, the majority of which (37 of 42) clustered across three metabolic superpathways (carbohydrates, amino acids, and nucleotides) and most functions (40 of 42) were associated with shorter OS. Multivariate analyses showed that dysfunction of carbohydrate metabolism had the most profound impact on OS [hazard ratio (HR) =5.208; 95% confidence interval (CI): 3.272 to 8.291], false discovery rate (FDR)-P≤0.0001, followed by amino acid metabolism (HR =3.346; 95% CI: 2.129 to 5.258), FDR-P≤0.0001 and nucleotide metabolism (HR =2.578; 95% CI: 1.598 to 4.159), FDR-P=0.0001. The deleterious effect of metabolic reprogramming on non-squamous NSCLC was observed independently of disease stage and across treatments groups.
Conclusions: By providing a detailed landscape of metabolic alterations in non-squamous NSCLC, our findings offer new insights in the biology of the disease and metabolic adaptation mechanisms of clinical significance.

Keywords:  Non-squamous non-small cell lung cancer; cancer metabolites; metabolic gene mutations; post-genomic pipeline

DOI:  https://doi.org/10.21037/tlcr-22-377
J Clin Med. 2022 Dec 31. pii: 321. [Epub ahead of print]12(1):

Impact of Type 2 Diabetes Mellitus on the Prognosis of Non-Small Cell Lung Cancer.

You Lu, Yaohua Hu, Yi Zhao, Shuanshuan Xie, Changhui Wang.

   OBJECTIVE: Type 2 diabetes mellitus (T2DM) is the most common metabolic disease and is characterized by sustained hyperglycemia. The impact of T2DM on the survival of lung cancer patients remains controversial. The aim of this study was to investigate the associations of type 2 diabetes with lung cancer mortality.
METHODS: From January 2019 to January 2020, 228 patients with non-small cell lung cancer (NSCLC) staging earlier than IIIA were included.
RESULTS: In our study, we found that the overall survival (OS) and progression-free survival (PFS) of lung cancer patients with diabetes was longer than non-diabetes group. Diagnosed T2DM was associated with the prognosis of lung cancer after adjusting for age and covariates. The association between T2DM and OS was influenced by age, stage of cancer and cancer treatment, as well as whether taking metformin was associated with the OS of lung cancer. However, with the adjustment for age and covariates, the relation trended to lose statistical significance.
CONCLUSION: T2DM is an independent prognostic factor for patients with NSCLC staging before IIIA. The patients with both NSCLC and T2DM trended to having a longer OS, possibly due to metformin.

Keywords:  diabetes; metformin; non-small cell lung cancer; prognosis

DOI:  https://doi.org/10.3390/jcm12010321
Cancer Diagn Progn. 2023 Jan-Feb;3(1):3(1): 44-52

Neutrophil-to-Lymphocyte Ratio Is a Major Prognostic Factor in Non-small Cell Lung Carcinoma Patients Undergoing First Line Immunotherapy With Pembrolizumab.

Francesco Jacopo Romano, Riccardo Ronga, Francesca Ambrosio, Dario Arundine, Vito Longo, Domenico Galetta, Cesare Gridelli, Paolo Maione, Valentina Palma, Vincenzo Damiano, Antonio Verde, Ilaria Giacobbe, Maria Rosaria Augurio, Gennaro Iengo, Massimiliano Chetta, Marina Tarsitano, Severo Campione, Giuseppe Failla, Antonio Raucci, Ferdinando Riccardi.

   BACKGROUND/AIM: Lung cancer is one of the most common malignant neoplastic diseases and by far the leading cause of cancer death worldwide. Recently, immune checkpoint inhibitors (ICIs) have received increasing attention for playing a crucial role in non-small cell lung cancer (NSCLC). Biomarkers, such as programmed cell death-ligand 1 (PD-L1) and tumor mutational burden (TMB), seemed to be helpful in selecting patients who are more likely to benefit from ICI treatment: however, their role has not yet been fully clarified.
PATIENTS AND METHODS: In this retrospective study, we evaluated the relationship between pre-treatment peripheral blood neutrophil-to-lymphocyte ratio (NLR) and survival in 252 patients suffering from advanced NSCLC who had received pembrolizumab as their first-line immunotherapy.
RESULTS: Compared to their NLR low counterparts who had a median overall survival (OS) of 34.8 months, patients with NLRs above 4.8 had a median OS of 7.6 months (HR=3.26, 95%Cl=2.3-4.6, p-value<0.0000001). In multivariate Cox regression analysis, alongside other variables, such as metastatic sites, age, and sex, NLR and PD-L1 predicted progression-free survival and OS; furthermore, a very high NLR - over 10 - seemed to forecast a very dismal prognosis in patients undergoing immunotherapy, with sudden deaths in the days immediately following therapy (median OS=3.8 months).
CONCLUSION: NLR acts as a valuable and reliable prognostic factor in non-small cell lung carcinoma patients undergoing first line immunotherapy with pembrolizumab. Additional investigation is necessary to fully elucidate the underlying biological rationale, which can be found in myeloid derived suppressor cells, a heterogeneous population of cells with neutrophil-like immunophenotypic features.

Keywords:  Non-small cell lung cancer; PD-L1; immunotherapy; leukocytosis; myeloid derived suppressor cells; neutrophils-to-lymphocytes ratio; pembrolizumab

DOI:  https://doi.org/10.21873/cdp.10178
Nat Commun. 2023 Jan 09. 14(1): 120

Tumor-intrinsic IRE1α signaling controls protective immunity in lung cancer.

Michael J P Crowley, Bhavneet Bhinder, Geoffrey J Markowitz, Mitchell Martin, Akanksha Verma, Tito A Sandoval, Chang-Suk Chae, Shira Yomtoubian, Yang Hu, Sahil Chopra, Diamile A Tavarez, Paolo Giovanelli, Dingcheng Gao, Timothy E McGraw, Nasser K Altorki, Olivier Elemento, Juan R Cubillos-Ruiz, Vivek Mittal.

IRE1α-XBP1 signaling is emerging as a central orchestrator of malignant progression and immunosuppression in various cancer types. Employing a computational XBP1s detection method applied to TCGA datasets, we demonstrate that expression of the XBP1s mRNA isoform predicts poor survival in non-small cell lung cancer (NSCLC) patients. Ablation of IRE1α in malignant cells delays tumor progression and extends survival in mouse models of NSCLC. This protective effect is accompanied by alterations in intratumoral immune cell subsets eliciting durable adaptive anti-cancer immunity. Mechanistically, cancer cell-intrinsic IRE1α activation sustains mPGES-1 expression, enabling production of the immunosuppressive lipid mediator prostaglandin E2. Accordingly, restoring mPGES-1 expression in IRE1αKO cancer cells rescues normal tumor progression. We have developed an IRE1α gene signature that predicts immune cell infiltration and overall survival in human NSCLC. Our study unveils an immunoregulatory role for cancer cell-intrinsic IRE1α activation and suggests that targeting this pathway may help enhance anti-tumor immunity in NSCLC.

DOI: https://doi.org/10.1038/s41467-022-35584-9
Lung Cancer. 2022 Dec 31. pii: S0169-5002(22)00740-1. [Epub ahead of print]176 103-111

Large-scale clinico-genomic profile of non-small cell lung cancer with KRAS G12C: Results from LC-SCRUM-Asia study.

Yutaro Tamiya, Shingo Matsumoto, Yoshitaka Zenke, Kiyotaka Yoh, Takaya Ikeda, Yuji Shibata, Terufumi Kato, Kazumi Nishino, Atsushi Nakamura, Naoki Furuya, Shingo Miyamoto, Shoichi Kuyama, Shogo Nomura, Takashi Ikeno, Hibiki Udagawa, Eri Sugiyama, Kaname Nosaki, Hiroki Izumi, Tetsuya Sakai, Naozumi Hashimoto, Koichi Goto.

   INTRODUCTION: KRAS G12C is an oncogenic driver mutation, accounting for approximately 14% of Caucasian patients with non-small cell lung cancer (NSCLC). Recently, several KRAS G12C-targeted drugs have been developed; however, the clinico-genomic characteristics of NSCLC patients with KRAS G12C remain unclear.
MATERIALS AND METHODS: Based on the large-scale prospective lung cancer genomic screening project (LC-SCRUM-Asia) database, the clinico-genomic characteristics and therapeutic outcomes of NSCLC patients with KRAS G12C were evaluated.
RESULTS: From March 2015 to March 2021, 10,023 NSCLC patients were enrolled in LC-SCRUM-Asia. KRAS mutations were detected in 1258 patients (14 %), including G12C in 376 (4.0 %), G12D in 289 (3.1 %) and G12V in 251 (2.7 %). The proportions of males and smokers were higher in patients with KRAS G12C than in those with KRAS non-G12C mutations (males: 73 % vs 63 %, p < 0.001; smokers: 89 % vs 76 %, p < 0.001). KRAS G12C-positive tumors showed a higher tumor mutation burden (TMB) (mean, 8.1 mut/Mb, p < 0.001) and a higher percentage of tumors with programmed cell death ligand-1 (PD-L1) expression ≥50 % (52 %, p = 0.08). The overall survival in patients with KRAS G12C (median, 24.6 months) was not different between patients with other mutation subtypes (G12V: 18.2 months, p = 0.23; G12D: 20.6 months, p = 0.65; other KRAS mutations: 18.3 months, p = 0.20). Among KRAS-mutated patients who received immune checkpoint inhibitors (ICIs), the progression-free survival in G12C-positive patients (median, 3.4 months) was similar to that in G12V-positive patients (4.2 months, p = 0.90), but significantly longer than that in G12D- (2.0 months, p = 0.02) and other KRAS mutation-positive patients (2.5 months, p = 0.02).
CONCLUSIONS: The frequencies of KRAS G12C were lower in Asian than in Caucasian NSCLC patients. Among the KRAS-mutated NSCLC patients, G12C-positive tumors showed increased immunogenicity, such as high TMB and high PD-L1 expression, and potential sensitivity to ICIs.

Keywords:  KRAS G12C; KRAS mutation; Next-generation sequencing; Non-small cell lung cancer; PD-L1 expression; Tumor burden

DOI:  https://doi.org/10.1016/j.lungcan.2022.12.019
Cell Commun Signal. 2023 Jan 13. 21(1): 9

Lower SLC7A2 expression is associated with enhanced multidrug resistance, less immune infiltrates and worse prognosis of NSCLC.

Shanshan Jiang, Junrong Zou, Jianyu Dong, Huimian Shi, Jie Chen, Yan Li, Xianglong Duan, Wensheng Li.

   BACKGROUND: Solute carrier family 7 member 2 (SLC7A2), a cationic amino acid transporter, is lowly expressed in ovarian and hepatocellular cancers, which is associated with their worse prognosis. However, its roles in the prognosis, drug resistance and immune infiltration in non-small-cell lung cancer (NSCLC) are unclear.
METHODS: We chose SLC7A2 from RNA-Seq of paclitaxel/cisplatin-resistant A549 cells, then bioinformatics, cell lines construction, RT-qPCR, and CCK8 were performed to investigate SLC7A2 role.
RESULT: We analyzed the 223 differentially expressed genes (DEGs) from RNA-Seq of paclitaxel/cisplatin-resistant A549 cells and found that SLC7A2 expression was down-regulated in NSCLC. Lower SLC7A2 expression was associated with worse recurrence-free survival (RFS) in NSCLC. SLC7A2 silencing enhanced the proliferation of NSCLC cells and their insensitivity to paclitaxel, cisplatin, and gemcitabine in vitro. Activation of AMPK has up-regulated SLC7A2 expression and enhanced the sensitivity of NSCLC cells to anti-tumor drugs, which could be attributed to E2F1's regulation. In addition, the levels of SLC7A2 expression were correlated to the numbers of infiltrated neutrophils, macrophages, dendritic cells and their marker genes, like CD86, HLA-DPA1 and ITGAM.
CONCLUSIONS: SLC7A2 may act as a tumor suppressor to modulate drug sensitivity, immune infiltration and survival in NSCLC. Video abstract.

Keywords:  AMPK; Immune infiltration; Multiple drug resistance; NSCLC; SLC7A2

DOI:  https://doi.org/10.1186/s12964-022-01023-x