bims-meluca 2022-04-10 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2022–04–10
eleven papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge and Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

The hexosamine pathway and coat complex II promote malignant adaptation to nutrient scarcity.
Metabolic profile of the Warburg effect as a tool for molecular prognosis and diagnosis of cancer.
Targeting nicotinamide N-methyltransferase overcomes resistance to EGFR-TKI in non-small cell lung cancer cells.
Predictive significance of inflammatory indexes in metastatic nonsmall cell lung cancer patients treated with platinum-doublet chemotherapy.
The role of pyroptosis in lung cancer and compounds regulated pyroptosis of lung cancer cells.
Inhibition of epidermal growth factor receptor suppresses parathyroid hormone-related protein expression in tumours and ameliorates cancer-associated cachexia.
Pretreatment body mass index predicts survival among patients administered nivolumab monotherapy for pretreated non-small cell lung cancer.
Bronchoalveolar lavage fluid reveals factors contributing to the efficacy of PD-1 blockade in lung cancer.
MTAP deficiency creates an exploitable target for antifolate therapy in 9p21-loss cancers.
Circular RNA circ_0061140 accelerates hypoxia-induced glycolysis, migration, and invasion in lung adenocarcinoma through the microRNA-653/hexokinase 2 (HK2) axis.
Nutritional support in lung cancer: Time to combine immunonutrition with immunotherapy?

Life Sci Alliance. 2022 Jul;pii: e202101334. [Epub ahead of print]5(7):

The hexosamine pathway and coat complex II promote malignant adaptation to nutrient scarcity.

Helena Dragic, Audrey Barthelaix, Cédric Duret, Simon Le Goupil, Hadrien Laprade, Sophie Martin, Sabine Brugière, Yohann Couté, Christelle Machon, Jerome Guitton, Justine Rudewicz, Paul Hofman, Serge Lebecque, Cedric Chaveroux, Carole Ferraro-Peyret, Toufic Renno, Serge N Manié.

The glucose-requiring hexosamine biosynthetic pathway (HBP), which produces UDP-N-acetylglucosamine for glycosylation reactions, promotes lung adenocarcinoma (LUAD) progression. However, lung tumor cells often reside in low-nutrient microenvironments, and whether the HBP is involved in the adaptation of LUAD to nutrient stress is unknown. Here, we show that the HBP and the coat complex II (COPII) play a key role in cell survival during glucose shortage. HBP up-regulation withstood low glucose-induced production of proteins bearing truncated N-glycans, in the endoplasmic reticulum. This function for the HBP, alongside COPII up-regulation, rescued cell surface expression of a subset of glycoproteins. Those included the epidermal growth factor receptor (EGFR), allowing an EGFR-dependent cell survival under low glucose in anchorage-independent growth. Accordingly, high expression of the HBP rate-limiting enzyme GFAT1 was associated with wild-type EGFR activation in LUAD patient samples. Notably, HBP and COPII up-regulation distinguished LUAD from the lung squamous-cell carcinoma subtype, thus uncovering adaptive mechanisms of LUAD to their harsh microenvironment.

DOI: https://doi.org/10.26508/lsa.202101334
Expert Rev Mol Diagn. 2022 Apr 08.

Metabolic profile of the Warburg effect as a tool for molecular prognosis and diagnosis of cancer.

Gerardo M Nava, Luis Alberto Madrigal Perez.

   INTRODUCTION: Adaptations of eukaryotic cells to environmental changes are important for their survival. However, under some circumstances, microenvironmental changes promote that eukaryotic cells utilize a metabolic signature resembling a unicellular organism named the Warburg effect. Most cancer cells share the Warburg effect displaying lactic fermentation and high glucose uptake. The Warburg effect also induces a metabolic rewiring stimulating glutamine consumption and lipid synthesis, also considered cancer hallmarks. Amino acid metabolism alteration due to the Warburg effect increases plasma levels of proline and branched-chain amino acids in several cancer types. Proline and lipids are probably used as electron transfer molecules in carcinogenic cells. In addition, branched-chain amino acids fuel the Krebs cycle, protein synthesis, and signaling in cancer cells.
AREAS COVERED: This review covers how metabolomics studies describe changes in some metabolites and proteins associated with the Warburg effect and related metabolic pathways.
EXPERT OPINION: In this review, we analyze the metabolic signature of the Warburg effect and related phenotypes and propose some Warburg effect-related metabolites and proteins (lactate, glucose uptake, glucose transporters, glutamine, branched-chain amino acids, proline, and some lipogenic enzymes) as promising cancer biomarkers.

Keywords:  Biomarker; Warburg effect; cancer; diagnosis; metabolism; molecular prognosis

DOI:  https://doi.org/10.1080/14737159.2022.2065196
Cell Death Discov. 2022 Apr 06. 8(1): 170

Targeting nicotinamide N-methyltransferase overcomes resistance to EGFR-TKI in non-small cell lung cancer cells.

Jun Wang, Xi Liu, Yuanfeng Huang, Pan Li, Minqiang Yang, Shanshan Zeng, Danyang Chen, Qian Wang, Hao Liu, Kai Luo, Jin Deng.

Activating mutations of epidermal growth factor receptor (EGFR) contributes to the progression of non-small cell lung cancer (NSCLC). EGFR tyrosine kinase inhibitor (TKI)-targeted therapy has become the standard treatment for NSCLC patients with EGFR-mutations. However, acquired resistance to these agents remains a major obstacle for managing NSCLC. Here, we investigated a novel strategy to overcome EGFR TKI resistance by targeting the nicotinamide N-methyltransferase (NNMT). Using iTRAQ-based quantitative proteomics analysis, we identified that NNMT was significantly increased in EGFR-TKI-resistant NSCLC cells. Moreover, we found that NNMT expression was increased in EGFR-TKI-resistant NSCLC tissue samples, and higher levels were correlated with shorter progression-free survival in EGFR-TKI-treated NSCLC patients. Knockdown of NNMT rendered EGFR-TKI-resistant cells more sensitive to EGFR-TKI, whereas overexpression of NNMT in EGFR-TKI-sensitive cells resulted in EGFR-TKI resistance. Mechanically, upregulation of NNMT increased c-myc expression via SIRT1-mediated c-myc deacetylation, which in turn promoted glycolysis and EGFR-TKI resistance. Furthermore, we demonstrated that the combination of NNMT inhibitor and EGFR-TKI strikingly suppressed the growth of EGFR-TKI-resistant NSCLC cells both in vitro and in vivo. In conclusion, our research indicated that NNMT overexpression is important for acquired resistance to EGFR-TKI and that targeting NNMT might be a potential therapeutic strategy to overcome resistance to EGFR TKI.

DOI: https://doi.org/10.1038/s41420-022-00966-x
J Cancer Res Ther. 2022 Jan-Mar;18(1):18(1): 220-223

Predictive significance of inflammatory indexes in metastatic nonsmall cell lung cancer patients treated with platinum-doublet chemotherapy.

Mesut Yilmaz, Ahmet Baran, Merve Korkmaz Yilmaz.

   Introduction: Lung cancer is the leading cause of cancer-related deaths, worldwide. Despite immune checkpoint inhibitors and targeted therapy have revolutionized the treatment of metastatic nonsmall cell lung cancer (NSCLC), a significant proportion of patients are still treated with platinum-based chemotherapy. It is widely noticed that systemic inflammation plays an important role in the development and progression of many solid tumors. In this study, we aimed to analyze the predictive role of the systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), and prognostic nutritional index (PNI) in patients with advanced NSCLC treated with first-line platinum-doublet chemotherapy.
Methods: We retrospectively collected data of patients treated with first-line therapy for metastatic NSCLC. All patients were treated with first-line platinum-doublet chemotherapy. The patients were grouped based on the median values of SII, PNI, and NLR. The Mann-Whitney U test was used for comparisons between groups.
Results: The chemotherapy response rate (RR) was 75% in all patients. RR is statistically significantly lower in high SII, low PNI, and high NLR groups.
Conclusions: High inflammatory indexes in metastatic NSCLC patients who were treated with platinum-doublet chemotherapy are related to low chemotherapy RR.

Keywords:  Inflammatory indexes; lung cancer; neutrophil-to-lymphocyte ratio; prognostic nutritional index; systemic immune-inflammation index

DOI:  https://doi.org/10.4103/jcrt.jcrt_1902_20
J Cancer Res Ther. 2021 Dec;17(7): 1596-1602

The role of pyroptosis in lung cancer and compounds regulated pyroptosis of lung cancer cells.

Feng Tian, Xueyang Chen, Ke Yin, Xiaoyan Lin, Yinghua Song.

  Pyroptosis is a caspase-1/3/4/5/8/11-mediated form of programmed cell death. It is primarily induced through two pathways - the canonical and noncanonical pathways. Following enzymatic cleavage, gasdermin D, a key substrate for pyroptosis, releases N-terminal fragments that form pores on the plasma membrane, triggering osmotic lysis, and eventually releases cytosolic material to trigger inflammatory responses. Various pyroptotic pathway mediators are involved in lung cancer initiation, proliferation, migration, and invasion, and an increasing number of anticancer compounds have been developed by regulating the pyroptotic pathway. This review aims to summarize recent progress in the understanding of the molecular mechanisms of pyroptosis and the association between pyroptotic-related molecules and lung cancer. Moreover, we discussed more than 10 compounds that exerted antitumor properties by inducing pyroptosis of lung cancer cells.

Keywords:  Anticancer compounds; gasdermin; lung cancer; pyroptosis

DOI:  https://doi.org/10.4103/jcrt.jcrt_614_21
J Cachexia Sarcopenia Muscle. 2022 Apr 04.

Inhibition of epidermal growth factor receptor suppresses parathyroid hormone-related protein expression in tumours and ameliorates cancer-associated cachexia.

Bahar Zehra Camurdanoglu Weber, Samet Agca, Aylin Domaniku, Sevval Nur Bilgic, Dilsad H Arabaci, Serkan Kir.

   BACKGROUND: Lung cancer is the primary cause of cancer deaths worldwide. Activation of epidermal growth factor receptor (EGFR) leads to lung cancer progression and poor prognosis while involuntary weight loss remains a major problem. Tumour-derived parathyroid hormone-related protein (PTHrP) emerged as a potential mediator of cachexia. Here, we investigated the modulatory role of EGFR signalling in PTHrP (encoded by Pthlh) gene expression and the impact of this relationship on cancer cachexia.
METHODS: Global gene expression profiles of Lewis lung carcinoma (LLC) cells were analysed. Pthlh mRNA levels were measured by qRT-PCR in LLC cells treated with EGFR ligands and tyrosine kinase inhibitors (TKIs). LLC tumour-bearing mice received EGFR TKI erlotinib for 7 days via intraperitoneal injection or oral gavage. Tumour Pthlh mRNA, weight of fat/muscle tissue, and grip strength were assessed. RNA-seq data from The Cancer Genome Atlas and gene expression analysis tools were used to characterize expression profiles of PTHLH and EGFR along with correlation analysis of PTHLH with EGFR and transforming growth factor alpha (TGFA) in human lung cancer and head and neck squamous carcinoma (HNSC). Survival of lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) patients with EGFR gene alterations was analysed in regard to PTHLH expression.
RESULTS: Expression of EGFR ligands, EGFR itself, and PTHrP co-clusters in LLC cells. Activation of EGFR signalling with its ligands significantly increases (3.8-fold, P < 0.0005) while EGFR TKIs significantly decrease (90%, P < 0.0005) Pthlh mRNA levels in LLC cells. Pthlh mRNA drops 65-75% (P < 0.0005) in tumours upon treatment of LLC tumour-bearing mice with erlotinib while their muscle mass and grip strength increase (9.2% P < 0.05, 23% P < 0.005, respectively) compared with tumour-bearing control mice. PTHLH is overexpressed in tumours of LUSC (45.8-fold, P < 0.05) and HNSC (17.5-fold, P < 0.05) compared with normal tissue. PTHLH expression correlates with EGFR and its ligand TGFA in both cancers (LUSC: n = 745, R = 0.32, P < 0.0001 and R = 0.51, P < 0.0001; HNSC: n = 545, R = 0.34, P < 0.001 and R = 0.50, P < 0.001, respectively). High PTHLH mRNA associates with poor overall survival in LUAD patients with activating EGFR mutations (n = 40, log-rank test, P = 0.0451).
CONCLUSIONS: Epidermal growth factor receptor signalling regulates expression of cachexia mediator PTHrP. EGFR inhibition reduces PTHrP expression in LLC tumours and ameliorates cachexia in LLC tumour-bearing mice.

Keywords:  Cancer-associated cachexia; EGFR inhibitors; Epidermal growth factor receptor (EGFR); Lung cancer; Parathyroid hormone-related protein (PTHrP)

DOI:  https://doi.org/10.1002/jcsm.12985
Thorac Cancer. 2022 Apr 08.

Pretreatment body mass index predicts survival among patients administered nivolumab monotherapy for pretreated non-small cell lung cancer.

Hisao Imai, Erika Naito, Ou Yamaguchi, Kosuke Hashimoto, Hidetoshi Iemura, Yu Miura, Ayako Shiono, Atsuto Mouri, Kyoichi Kaira, Kunihiko Kobayashi, Hiroshi Kagamu.

   BACKGROUND: Biomarker assessments for nivolumab monotherapy efficacy in previously treated patients with non-small cell lung cancer (NSCLC) remain unclear. We evaluated whether body mass index (BMI) and Glasgow prognostic score (GPS) are useful for assessing the efficacy of nivolumab alone as a second-line treatment in patients with pretreated NSCLC.
METHODS: Data of 99 patients treated with second-line nivolumab monotherapy for NSCLC between January 2016 and December 2019 were evaluated for prognostic values of BMI and GPS to assess their usefulness in predicting progression-free survival (PFS) and overall survival (OS).
RESULTS: The Eastern Cooperative Oncology Group-performance status (PS) independently predicted the second-line nivolumab monotherapeutic effect; good PS (0-1) correlated with significantly longer PFS (4.3 vs. 1.9 months, log-rank; p = 0.0004) and OS (17.7 vs. 4.6 months, log-rank; p < 0.0001) than poor PS. BMI independently predicted survival, with high BMI (≥22.1 kg/m2 ) associated with significantly longer OS (19.1 vs. 8.5 months, log-rank; p = 0.0023) than low BMI (<22.1 kg/m2 ). However, GPS showed no significant difference for PFS or OS.
CONCLUSION: Among patients with NSCLC treated with nivolumab monotherapy as second-line treatment, PS was significantly correlated with both PFS and OS and BMI with OS. Thus, BMI could be a useful predictor of survival in these patients.

Keywords:  body mass index; carcinoma; glasgow prognostic score; nivolumab; non-small-cell lung; performance status; survival

DOI:  https://doi.org/10.1111/1759-7714.14417
JCI Insight. 2022 Apr 07. pii: e157915. [Epub ahead of print]

Bronchoalveolar lavage fluid reveals factors contributing to the efficacy of PD-1 blockade in lung cancer.

Kentaro Masuhiro, Motohiro Tamiya, Kosuke Fujimoto, Shohei Koyama, Yujiro Naito, Akio Osa, Takashi Hirai, Hidekazu Suzuki, Norio Okamoto, Takayuki Shiroyama, Kazumi Nishino, Yuichi Adachi, Takuro Nii, Yumi Kinugasa-Katayama, Akiko Kajihara, Takayoshi Morita, Seiya Imoto, Satoshi Uematsu, Takuma Irie, Daisuke Okuzaki, Taiki Aoshi, Yoshito Takeda, Toru Kumagai, Tomonori Hirashima, Atsushi Kumanogoh.

  Bronchoalveolar lavage is commonly performed to assess inflammation and identify responsible pathogens in lung diseases, and its findings might be used to evaluate the immune profile of the lung tumor microenvironment (TME). To investigate whether bronchoalveolar lavage fluid (BALF) analysis can help identify non-small cell lung cancer (NSCLC) patients who respond to immune checkpoint inhibitors (ICIs), BALF and blood were prospectively collected before initiating nivolumab. The secreted molecules, microbiome, and cellular profiles based on BALF and blood analysis were compared regarding therapeutic effect in 12 patients. Compared to ICI non-responders, responders showed significantly higher CXCL9 levels and a greater diversity of the lung microbiome profile in BALF, along with a greater frequency of the CD56+ subset in blood T cells, whereas no significant difference in PD-L1 expression was found in tumor cells. Antibiotic treatment in a preclinical lung cancer model significantly decreased CXCL9 in the lung TME, resulting in reduced sensitivity to anti-PD-1 antibody, which was reversed by CXCL9 induction in tumor cells. Thus, CXCL9 might be associated with the lung TME microbiome, and their balance could contribute to nivolumab sensitivity in NSCLC patients. BALF analysis can help predict the efficacy of ICIs when performed along with currently approved examinations.

Keywords:  Cancer immunotherapy; Chemokines; Immunology; Lung cancer; Oncology

DOI:  https://doi.org/10.1172/jci.insight.157915
Nat Commun. 2022 Apr 04. 13(1): 1797

MTAP deficiency creates an exploitable target for antifolate therapy in 9p21-loss cancers.

Omar Alhalabi, Jianfeng Chen, Yuxue Zhang, Yang Lu, Qi Wang, Sumankalai Ramachandran, Rebecca Slack Tidwell, Guangchun Han, Xinmiao Yan, Jieru Meng, Ruiping Wang, Anh G Hoang, Wei-Lien Wang, Jian Song, Lidia Lopez, Alex Andreev-Drakhlin, Arlene Siefker-Radtke, Xinqiao Zhang, William F Benedict, Amishi Y Shah, Jennifer Wang, Pavlos Msaouel, Miao Zhang, Charles C Guo, Bogdan Czerniak, Carmen Behrens, Luisa Soto, Vassiliki Papadimitrakopoulou, Jeff Lewis, Waree Rinsurongkawong, Vadeerat Rinsurongkawong, Jack Lee, Jack Roth, Stephen Swisher, Ignacio Wistuba, John Heymach, Jing Wang, Matthew T Campbell, Eleni Efstathiou, Mark Titus, Christopher J Logothetis, Thai H Ho, Jianjun Zhang, Linghua Wang, Jianjun Gao.

Methylthioadenosine phosphorylase, an essential enzyme for the adenine salvage pathway, is often deficient (MTAPdef) in tumors with 9p21 loss and hypothetically renders tumors susceptible to synthetic lethality by antifolates targeting de novo purine synthesis. Here we report our single arm phase II trial (NCT02693717) that assesses pemetrexed in MTAPdef urothelial carcinoma (UC) with the primary endpoint of overall response rate (ORR). Three of 7 enrolled MTAPdef patients show response to pemetrexed (ORR 43%). Furthermore, a historic cohort shows 4 of 4 MTAPdef patients respond to pemetrexed as compared to 1 of 10 MTAP-proficient patients. In vitro and in vivo preclinical data using UC cell lines demonstrate increased sensitivity to pemetrexed by inducing DNA damage, and distorting nucleotide pools. In addition, MTAP-knockdown increases sensitivity to pemetrexed. Furthermore, in a lung adenocarcinoma retrospective cohort (N = 72) from the published BATTLE2 clinical trial (NCT01248247), MTAPdef associates with an improved response rate to pemetrexed. Our data demonstrate a synthetic lethal interaction between MTAPdef and de novo purine inhibition, which represents a promising therapeutic strategy for larger prospective trials.

DOI: https://doi.org/10.1038/s41467-022-29397-z
Bioengineered. 2022 Apr 05.

Circular RNA circ_0061140 accelerates hypoxia-induced glycolysis, migration, and invasion in lung adenocarcinoma through the microRNA-653/hexokinase 2 (HK2) axis.

Shaobin Wang, Hao Zhang, Lixia Xia, Fen Lan.

  Circular RNA (circRNA) is considered to be an essential regulator of multiple human malignancies. However, the role and molecular mechanism of circ_0061140 in lung adenocarcinoma ((LUAD) remain elusive. The levels of circ_0061140, microRNA (miR)-653 and hexokinase 2 (HK2) were examined by RT-qPCR. Downstream targets of circ_0061140 were predicted by circinteractome website and verified by luciferase reporter and RIP assays. HK2 protein level was assessed via western blotting. The migratory and invasive abilities of LUAD cells were assessed via wound healing and transwell assays. It was uncovered that circ_0061140 level was elevated in LUAD samples, and the high level of circ_0061140 was related to poor survival rate of LUAD patients. Circ_0061140 deletion inhibited glycolysis, migration and invasion of hypoxia-treated LUAD cells. Moreover, circ_0061140 could modulate HK2 level by absorbing miR-653. Furthermore, miR-653 silence or HK2 addition neutralized the effects of circ_0061140 knockdown on LUAD progression under hypoxia. This study elaborated that circ_0061140 accelerated hypoxia-triggered glycolysis, migration and invasion in LUAD cells via downregulating miR-653 and increasing HK2 expression.

Keywords:  HK2; circ_0061140; lung adenocarcinoma; miR-653

DOI:  https://doi.org/10.1080/21655979.2021.2000743
Nutrition. 2022 Mar 03. pii: S0899-9007(22)00050-8. [Epub ahead of print]98 111637

Nutritional support in lung cancer: Time to combine immunonutrition with immunotherapy?

Sara Pilotto, Francesco Agustoni, Anna Maria Morelli, Federica Lobascio, Emanuele Cereda, Paolo Bironzo, Ilaria Trestini, Michele Milella, Silvia Novello, Paolo Pedrazzoli, Riccardo Caccialanza.

  Although there is substantial evidence on the impact of nutritional-status deterioration on quality of life, treatment tolerance, morbidity, and mortality in people with cancer, clinical nutrition intervention trials in oncology are still limited. The rationale for deepening this topic is also justified by the availability of innovative treatment options, such as immunotherapy, which take into consideration potential modulation of the immune system by several factors. In this article, we aimed to focus on the unexplored issue of immunonutrition and its potential modulatory activity on treatment response in people receiving immunotherapy. With this perspective, we propose a clinical-trial model to explore the potential impact of immunonutrition on nutritional, functional, immunologic, safety, and efficacy parameters in people with advanced non-small cell lung cancer undergoing first-line immunotherapy-based anticancer treatment.

Keywords:  Immunonutrition; Immunotherapy; Lung cancer; Malnutrition; Nutritional support

DOI:  https://doi.org/10.1016/j.nut.2022.111637