bims-meluca 2023-03-26 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2023–03–26
seven papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Role and therapeutic targeting of glutamine metabolism in non‑small cell lung cancer (Review).
Histone deacetylase 6 inhibition exploits selective metabolic vulnerabilities in LKB1 mutant, KRAS driven non-small cell lung cancer.
Changes of tumor microenvironment in non-small cell lung cancer after TKI treatments.
Rethinking glutamine metabolism and the regulation of glutamine addiction by oncogenes in cancer.
RTKN2 Inhibits the Growth, Migration, Invasion and Glycolysis of Lung Adenocarcinoma Cells by Inactivating the NF-κB Signalling Pathway.
Metformin regulates expression of DNA methyltransferases through the miR-148/-152 family in non-small lung cancer cells.
Classification of Tumor Immune Microenvironment (TIME) According to PD-L1 Expression and Immune Infiltration Predicts Response to Immunotherapy plus Chemotherapy in Advanced NSCLC Patients.

Oncol Lett. 2023 Apr;25(4): 159

Role and therapeutic targeting of glutamine metabolism in non‑small cell lung cancer (Review).

Lei Zhou, Qi Zhang, Qing Zhu, Yuan Zhan, Yong Li, Xuan Huang.

  The Warburg effect indicates that cancer cells survive through glycolysis under aerobic conditions; as such, the topic of cancer metabolism has aroused interest. It is requisite to further explore cancer metabolism, as it helps to simultaneously explain the process of carcinogenesis and guide therapy. The flexible metabolism of cancer cells, which is the result of metabolic reprogramming, can meet the basic needs of cells, even in a nutrition-deficient environment. Glutamine is the most abundant non-essential amino acid in the circulation, and along with glucose, comprise the two basic nutrients of cancer cell metabolism. Glutamine is crucial in non-small cell lung cancer (NSCLC) cells and serves an important role in supporting cell growth, activating signal transduction and maintaining redox homeostasis. In this perspective, the present review aims to provide a new therapeutic strategy of NSCLC through inhibiting the metabolism of glutamine. This review not only summarizes the significance of glutamine metabolism in NSCLC cells, but also enumerates traditional glutamine inhibitors along with new targets. It also puts forward the concept of combination therapy and patient stratification with the aim of comprehensively showing the effect and prospect of targeted glutamine metabolism in NSCLC therapy. This review was completed by searching for keywords including 'glutamine', 'NSCLC' and 'therapy' on PubMed, and screening out articles.

Keywords:  Warburg effect; glutamine metabolism; metabolism inhibitor; non-small cell lung cancer; therapeutic strategies

DOI:  https://doi.org/10.3892/ol.2023.13745
J Thorac Oncol. 2023 Mar 21. pii: S1556-0864(23)00197-1. [Epub ahead of print]

Histone deacetylase 6 inhibition exploits selective metabolic vulnerabilities in LKB1 mutant, KRAS driven non-small cell lung cancer.

Hua Zhang, Christopher S Nabel, Dezhi Li, Ruth Í O'Connor, Caroline R Crosby, Sarah M Chang, Yuan Hao, Robyn Stanley, Soumyadip Sahu, Daniel S Levin, Ting Chen, Sittinon Tang, Hsin-Yi Huang, Mary Meynardie, Janaye Stephens, Fiona Sherman, Alison Chafitz, Naoise Costelloe, Daniel A Rodrigues, Hilda Fogarty, Miranda G Kiernan, Fiona Cronin, Eleni Papadopoulos, Magdalena Ploszaj, Vajira Weerasekara, Jiehui Deng, Patrick Kiely, Nabeel Bardeesy, Matthew G Vander Heiden, Triona Ni Chonghaile, Catríona M Dowling, Kwok-Kin Wong.

   INTRODUCTION: In KRAS-mutant non-small lung cancer (NSCLC), co-occurring alterations in LKB1 confer a negative prognosis compared to other mutations such as TP53. LKB1 is a tumor suppressor that coordinates several signaling pathways in response to energetic stress. Our recent work on pharmacologic and genetical inhibition of HDAC6 demonstrated impaired activity of numerous enzymes involved in glycolysis. Based on these prior findings, we explored the therapeutic window for HDAC6 inhibition in metabolically-active KRAS-mutant lung tumors.
EXPERIMENTAL DESIGN: Using cell lines derived from mouse autochthonous tumors bearing the KRAS/LKB1 (KL) and KRAS/TP53 (KP) mutant genotypes to control for confounding germline and somatic mutations in human models, we characterize the metabolic phenotypes at baseline and in response to HDAC6 inhibition. The impact of HDAC6 inhibition was measured on cancer cell growth in vitro and on tumor growth in vivo.
RESULTS: Surprisingly, KL-mutant cells demonstrated reduced levels of redox-sensitive cofactors at baseline. This associated with increased sensitivity to pharmacologic HDAC6 inhibition with ACY-1215 and blunted ability to increase compensatory metabolism and buffer oxidative stress. Seeking synergistic metabolic combination treatments, we found enhanced cell killing and anti-tumor efficacy with glutaminase inhibition in KL lung cancer models in vitro and in vivo.
CONCLUSIONS: Exploring the differential metabolism of KL and KP mutant NSCLC, we identified decreased metabolic reserve in KL mutant tumors. HDAC6 inhibition exploited a therapeutic window in KL NSCLC based on a diminished ability to compensate for impaired glycolysis, nominating a novel strategy for treatment of KRAS-mutant NSCLC with co-occurring LKB1 mutations.

Keywords:  HDAC6; KRAS; LKB1; TP53; glutaminase inhibition; glycolysis; non-small cell lung cancer; oxidative stress

DOI:  https://doi.org/10.1016/j.jtho.2023.03.014
Front Immunol. 2023 ;14 1094764

Changes of tumor microenvironment in non-small cell lung cancer after TKI treatments.

Shanshan Chen, Jingyi Tang, Fen Liu, Wei Li, Ting Yan, Dangang Shangguan, Nong Yang, Dehua Liao.

  Non-small cell lung cancer (NSCLC) is the most common lung cancer diagnosis, among which epidermal growth factor receptor (EGFR), Kirsten rat sarcoma (KRAS), and anaplastic lymphoma kinase (ALK) mutations are the common genetic drivers. Their relative tyrosine kinase inhibitors (TKIs) have shown a better response for oncogene-driven NSCLC than chemotherapy. However, the development of resistance is inevitable following the treatments, which need a new strategy urgently. Although immunotherapy, a hot topic for cancer therapy, has shown an excellent response for other cancers, few responses for oncogene-driven NSCLC have been presented from the existing evidence, including clinical studies. Recently, the tumor microenvironment (TME) is increasingly thought to be a key parameter for the efficacy of cancer treatment such as targeted therapy or immunotherapy, while evidence has also shown that the TME could be affected by multi-factors, such as TKIs. Here, we discuss changes in the TME in NSCLC after TKI treatments, especially for EGFR-TKIs, to offer information for a new therapy of oncogene-driven NSCLC.

Keywords:  ICIs - immune checkpoint inhibitors; driver mutation; non-small cell lung cancer; tumor microenvironment; tyrosine kinase inhibitor

DOI:  https://doi.org/10.3389/fimmu.2023.1094764
Front Oncol. 2023 ;13 1143798

Rethinking glutamine metabolism and the regulation of glutamine addiction by oncogenes in cancer.

Rui Ni, Ziwei Li, Li Li, Dan Peng, Yue Ming, Lin Li, Yao Liu.

  Glutamine, the most abundant non-essential amino acid in human blood, is crucial for cancer cell growth and cancer progression. Glutamine mainly functions as a carbon and nitrogen source for biosynthesis, energy metabolism, and redox homeostasis maintenance in cancer cells. Dysregulated glutamine metabolism is a notable metabolic characteristic of cancer cells. Some carcinogen-driven cancers exhibit a marked dependence on glutamine, also known as glutamine addiction, which has rendered the glutamine metabolic pathway a breakpoint in cancer therapeutics. However, some cancer cells can adapt to the glutamine unavailability by reprogramming metabolism, thus limiting the success of this therapeutic approach. Given the complexity of metabolic networks and the limited impact of inhibiting glutamine metabolism alone, the combination of glutamine metabolism inhibition and other therapeutic methods may outperform corresponding monotherapies in the treatment of cancers. This review summarizes the uptake, transport, and metabolic characteristics of glutamine, as well as the regulation of glutamine dependence by some important oncogenes in various cancers to emphasize the therapeutic potential of targeting glutamine metabolism. Furthermore, we discuss a glutamine metabolic pathway, the glutaminase II pathway, that has been substantially overlooked. Finally, we discuss the applicability of polytherapeutic strategies targeting glutamine metabolism to provide a new perspective on cancer therapeutics.

Keywords:  cancer therapy; glutamine addiction; glutamine metabolism; metabolism inhibiton; oncogene

DOI:  https://doi.org/10.3389/fonc.2023.1143798
Biochem Genet. 2023 Mar 23.

RTKN2 Inhibits the Growth, Migration, Invasion and Glycolysis of Lung Adenocarcinoma Cells by Inactivating the NF-κB Signalling Pathway.

Na Wang, Jinxiang Wang.

   BACKGROUND: Lung adenocarcinoma (LUAD) is a malignant tumour that seriously threatens the life and health of people worldwide. This research was carried out to investigate the role of Rhotekin 2 (RTKN2) in LUAD progression.
METHODS AND RESULTS: The GEPIA online database was used to analyse abnormally expressed genes in lung adenocarcinoma and RTKN2 expression in various cancers. Cell proliferation was detected with CCK-8 and colony formation assays. Transwell assays were carried out to assess cell migration and invasion. The extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) were evaluated by a Seahorse XFe96 analyser. The interaction between RTKN2 and p65 was confirmed using a coimmunoprecipitation assay. RTKN2 expression was detected with qPCR, immunohistochemistry, and western blot assays. The p65 levels in the cytoplasm and nucleus were determined by western blot assays. RTKN2 levels were prominently decreased in LUAD tissues and cell lines. RTKN2 overexpression suppressed LUAD cell growth, invasion, migration, and glycolysis, while RTKN2 knockdown showed the opposite effects. Additionally, p65 could be negatively regulated by RTKN2. RTKN2 overexpression increased p65 levels in the cytoplasm but decreased p65 levels in the nucleus. Furthermore, blocking the NF-κB signalling pathway neutralized the effect of RTKN2 silencing in LUAD cells.
CONCLUSION: RTKN2 inhibited the malignant behaviour and glycolysis of LUAD cells by blocking the NF-κB signalling pathway, implying that RTKN2 could be a cancer suppressor in LUAD progression.

Keywords:  Glycolysis; Lung adenocarcinoma; NF-Κb; RTKN2; p65

DOI:  https://doi.org/10.1007/s10528-023-10352-6
Clin Epigenetics. 2023 Mar 23. 15(1): 48

Metformin regulates expression of DNA methyltransferases through the miR-148/-152 family in non-small lung cancer cells.

Bo Bin Lee, Dongho Kim, Yujin Kim, Joungho Han, Young Mog Shim, Duk-Hwan Kim.

   BACKGROUND: To understand the molecular mechanisms involved in regulation of DNA methyltransferases (DNMTs) by metformin in non-small cell lung cancer (NSCLC) cells.
METHODS: Expression levels of DNMTs in response to metformin were analyzed in NSCLC cells. MicroRNAs regulating expression of DNMTs at the post-transcriptional level were searched using miRNA-target databases (miRDB and miRTarBase), TCGA RNASeqV2 lung cancer data, and miRNA-seq.
RESULTS: Metformin dose-dependently downregulated expression of DNMT1 and DNMT3a at the post-transcriptional level and expression of DNMT3b at the transcriptional level in A549 lung cancer cells. Activity of DNMTs was reduced by about 2.6-fold in A549 cells treated with 10 mM metformin for 72 h. miR-148/-152 family members (miR-148a, miR-148b, and miR-152) targeting the 3'UTR of DNMTs were associated with post-transcriptional regulation of DNMTs by metformin. Metformin upregulated expression of miR-148a, miR-148b, and miR-152 in A549 and H1650 cells. Transfection with an miR-148b plasmid or a mimic suppressed expression of DNMT1 and DNMT3b in A549 cells. Transfection with the miR-148a mimic in A549 and H1650 cells decreased the luciferase activity of DNMT1 3'UTR. A combination of metformin and cisplatin synergistically increased expression levels of miR-148/-152 family members but decreased expression of DNMTs in A549 cells. Low expression of miR-148b was associated with poor overall survival (HR = 2.56, 95% CI 1.09-6.47; P = 0.04) but not with recurrence-free survival.
CONCLUSIONS: The present study suggests that metformin inhibits expression of DNMTs by upregulating miR-148/-152 family members in NSCLC cells.

Keywords:  DNMTs; Lung cancer; Metformin; Survival; microRNAs

DOI:  https://doi.org/10.1186/s13148-023-01466-0
J Thorac Oncol. 2023 Mar 20. pii: S1556-0864(23)00194-6. [Epub ahead of print]

Classification of Tumor Immune Microenvironment (TIME) According to PD-L1 Expression and Immune Infiltration Predicts Response to Immunotherapy plus Chemotherapy in Advanced NSCLC Patients.

Dongchen Sun, Jiaqing Liu, Huaqiang Zhou, Mengting Shi, Jiya Sun, Shen Zhao, Gang Chen, Yaxiong Zhang, Ting Zhou, Yuxiang Ma, Yuanyuan Zhao, Wenfeng Fang, Hongyun Zhao, Yan Huang, Yunpeng Yang, Li Zhang.

   BACKGROUND: According to mechanisms of adaptive immune resistance, tumor immune microenvironment (TIME) is classified into four types: PD-L1-/TIL- (type I); PD-L1+/TIL+ (type II); PD-L1-/TIL+ (type III); and PD-L1+/TIL- (type IV). However, the relationship of TIME classification model and immunotherapy efficacy has not been validated by any large-scale randomized controlled clinical trial among patients with advanced non-small cell lung cancer (NSCLC).
METHODS: Based on RNA-sequencing and immunohistochemistry data from ORIENT-11 study, we optimized TIME classification model and evaluated its predictive value for efficacy of immunotherapy plus chemotherapy.
RESULTS: PD-L1 mRNA expression and immune score calculated by the ESTIMATE method were strongest predictors for efficacy of immunotherapy plus chemotherapy. Therefore, they were determined as optimized definition of TIME classification system. When compared between combination therapy and chemotherapy alone, only type II subpopulation with high immune score and high PD-L1 mRNA expression was significantly associated with improved PFS (HR, 0.12; 95% CI, 0.06-0.25; P<.001) and OS (HR, 0.27; 95% CI, 0.13-0.55; P<.001). In combination group, type II subpopulation had much longer survival time, not even reaching median PFS or OS, but the other three subpopulations were prone to have similar PFS. In chemotherapy group, there was no significant association between survival outcomes and TIME subtypes.
CONCLUSION: Only patients with both high PD-L1 expression and high immune infiltration could benefit from chemotherapy plus immunotherapy in first-line treatment of advanced NSCLC. For patients lacking either PD-L1 expression or immune infiltration, chemotherapy alone might be a better treatment option to avoid unnecessary toxicities and financial burdens.

Keywords:  Non-small cell lung cancer (NSCLC); PD-1/PD-L1 (programmed cell death protein-1/programmed death-ligand 1); immunotherapy combined with chemotherapy; tumor immune infiltration; tumor immune microenvironment (TIME)

DOI:  https://doi.org/10.1016/j.jtho.2023.03.012