bims-meluca 2022-07-17 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2022–07–17
nine 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

Insight of a Metabolic Prognostic Model to Identify Tumor Environment and Drug Vulnerability for Lung Adenocarcinoma.
Serum immune modulators associated with immune-related toxicities and efficacy of atezolizumab in patients with non-small cell lung cancer.
Prospective assessment using 18F-FDG PET/CT as a novel predictor for early response to PD-1 blockade in non-small-cell lung cancer.
A novel prognostic signature of metastasis-associated genes and personalized therapeutic strategy for lung adenocarcinoma patients.
Clustering analysis and prognostic signature of lung adenocarcinoma based on the tumor microenvironment.
KRAS-G12D mutation drives immune suppression and the primary resistance of anti-PD-1/PD-L1 immunotherapy in non-small cell lung cancer.
High expression of PTGES3 is an independent predictive poor prognostic biomarker and correlates with immune infiltrates in lung adenocarcinoma.
Identification of Grb2-associated binding protein 3 expression to predict clinical outcomes and immunotherapeutic responses in lung adenocarcinoma.
Targeting STT3A produces an anti-tumor effect in lung adenocarcinoma by blocking the MAPK and PI3K/AKT signaling pathway.

Front Immunol. 2022 ;13 872910

Insight of a Metabolic Prognostic Model to Identify Tumor Environment and Drug Vulnerability for Lung Adenocarcinoma.

Shun-Li Peng, Rong Wang, Yu-Ling Zhou, Wei Wei, Gui-Hua Zhong, Xiao-Tao Huang, Shuai Yang, Qiao-Dan Liu, Zhi-Gang Liu.

  Metabolic reprogramming is a novel method for the treatment of malignant tumors. The exploration of metabolism procedures between radiosensitive and radioresistant tumors may provide novel perspectives for lung adenocarcinoma (LUAD) patients after radiation therapy. In our study, metabolic reprogramming and immune response changes were found between radioresistant cell line (A549RR) and its parent cells (A549) using gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Nucleotide/amino acid, lipid, and glucose metabolic process, including Alanine, aspartate and glutamate metabolism, Tryptophan/Tyrosine metabolism, Butanoate metabolism, Purine/Pyrimidine metabolism, were screened out. Then molecular signatures database and The Cancer Genome Atlas Program (TCGA) lung adenocarcinoma datasets were used to identify metabolism-related genes (MRGs) between radiosensitive and radioresistant lung adenocarcinoma (LUAD) cells. A metabolism-based prognostic model, receiver operating characteristic (ROC) curve and nomogram were constructed using Metabolism Score calculated by 14 metabolism-related genes (MRGs). Three independent public datasets, (GSE72094, GSE3141, GSE8894) and one immunotherapy cohort (IMvigor210) were used as external validation cohorts. Expression of 14 hub genes in cells, normal and LUAD specimens were explored by Human Protein Atlas, TIMER2.0 and RT-qPCR. Patients with low-Metabolism Scores were correlated with longer survival times, higher response rates to immune checkpoint inhibitors (ICIs), different immune cell infiltrations and drug vulnerability. Our study demonstrated a comprehensive landscape between radiosensitive and radioresistant LUAD, and provide novel targets for NSCLC, especially those patients received radiation therapy. Moreover, this metabolism-based prognostic model may help to investigate connections between radiosensitivity, immune response, metabolic reprogramming, and patients' prognosis.

Keywords:   metabolic signature; immune response; non-small cell lung cancer; prognostic model; radiosensitivity

DOI:  https://doi.org/10.3389/fimmu.2022.872910
J Cancer Res Clin Oncol. 2022 Jul 14.

Serum immune modulators associated with immune-related toxicities and efficacy of atezolizumab in patients with non-small cell lung cancer.

Yusuke Inoue, Naoki Inui, Masato Karayama, Kazuhiro Asada, Shun Matsuura, Masaki Ikeda, Tomohiro Uto, Masato Fujii, Dai Hashimoto, Takashi Matsui, Hiroyuki Matsuda, Nao Inami, Mikio Toyoshima, Yusuke Kaida, Hideki Yasui, Hironao Hozumi, Yuzo Suzuki, Kazuki Furuhashi, Noriyuki Enomoto, Tomoyuki Fujisawa, Takafumi Suda.

   PURPOSE: Identifying patients at high risk of immune-related adverse events (irAEs) that impede the achievement of durable efficacy of programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) blockade therapy is important in improving their management. Identification of a novel predictive factor of therapeutic benefit is also important in improving patient selection for treatment with PD-1/PD-L1 inhibitors. Further determinants driving response and linking with irAEs are urgently required.
METHODS: To address these unmet needs in the field, we explored whether 27 soluble checkpoint proteins and immunomodulatory proteins in serum at the therapy baseline and after week 3 were associated with irAE onset and therapeutic efficacy using MILLIPLEX Human Immuno-Oncology Checkpoint Protein Panel assays in a prospective, multicenter cohort of 81 patients with non-small cell lung cancer (NSCLC) receiving atezolizumab monotherapy.
RESULTS: By competing-risks regression analysis, we identified that high levels of B cell-activating factor (BAFF) at baseline were a significant and strong risk factor of irAEs (hazard ratio, 5.61; 95% confidence interval, 2.43-12.96; P < 0.0001). We also identified that increased inducible T cell co-stimulator (ICOS) during the first therapeutic cycle was an independent factor associated with prolonged progression-free survival and overall survival.
CONCLUSION: These findings are in keeping with the reported mechanistic basis of these molecules and may provide potential guidance for clinical decision-making to improve patient care. Further validation studies are warranted. Trial registration UMIN000035616 (January 28, 2019).

Keywords:  Atezolizumab; B cell-activating factor (BAFF); Immune-related adverse events (irAEs); Inducible T cell co-stimulator (ICOS); Non-small cell lung cancer; Serum immune modulators

DOI:  https://doi.org/10.1007/s00432-022-04193-w
Sci Rep. 2022 Jul 12. 12(1): 11832

Prospective assessment using 18F-FDG PET/CT as a novel predictor for early response to PD-1 blockade in non-small-cell lung cancer.

Ou Yamaguchi, Kyoichi Kaira, Ichiro Naruse, Yukihiro Umeda, Takeshi Honda, Satoshi Watanabe, Kosuke Ichikawa, Kazunari Tateishi, Norimitsu Kasahara, Tetsuya Higuchi, Kosuke Hashimoto, Shun Shinomiya, Yu Miura, Ayako Shiono, Atsuto Mouri, Hisao Imai, Kunihiko Iizuka, Tamotsu Ishizuka, Koichi Minato, Satoshi Suda, Hiroshi Kagamu, Keita Mori, Ichiei Kuji, Nobuhiko Seki.

Anti-programmed death-1 (PD-1) blockade is a standard treatment for advanced non-small-cell lung cancer (NSCLC). However, no appropriate modality exists for monitoring its therapeutic response immediately after initiation. Therefore, we aimed to elucidate the clinical relevance of 18F-FDG PET/CT versus CT in predicting the response to PD-1 blockade in the early phase. This prospective study included a total of 54 NSCLC patients. 18F-FDG PET/CT was performed at 4 weeks and 9 weeks after PD-1 blockade monotherapy. Maximum standardized uptake values (SULmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were evaluated. Among all patients, partial metabolic response and progressive metabolic disease after PD-1 blockade were observed in 35.2% and 11.1% on SULmax, 22.2% and 51.8% on MTV, and 27.8% and 46.3% on TLG, respectively, whereas a partial response (PR) and progressive disease (PD), respectively, based on RECIST v1.1 were recognized in 35.2% and 35.2%, respectively. The predictive probability of PR (MTV: 57.9% vs. 21.1%, p = 0.044; TLG: 63.2% vs. 21.1%, p = 0.020) and PD (MTV: 78.9% vs. 47.3%, p = 0.002; TLG: 73.7% vs. 21.1%, p = 0.007) detected based on RECIST at 4 weeks after PD-1 blockade initiation was significantly higher using MTV or TLG on 18F-FDG uptake than on CT. Multivariate analysis revealed that metabolic response by MTV or TLG at 4 weeks was an independent factor for response to PD-1 blockade treatment. Metabolic assessment by MTV or TLG was superior to morphological changes on CT for predicting the therapeutic response and survival at 4 weeks after PD-1 blockade.

DOI: https://doi.org/10.1038/s41598-022-15964-3
Aging (Albany NY). 2022 Jul 12. 14(undefined):

A novel prognostic signature of metastasis-associated genes and personalized therapeutic strategy for lung adenocarcinoma patients.

Zhihao Wang, Yusi Liu, Xiaoqian Zhan, Xi Wang, Chao Zhang, Lingzhi Qin, Liwei Liu, Shenghui Qin.

  Lung adenocarcinoma (LUAD) is a highly invasive and metastatic malignant tumor with high morbidity and mortality. This study aimed to construct a prognostic signature for LUAD patients based on metastasis-associated genes (MAGs). RNA expression profiles were downloaded from the Cancer Genome Atlas (TCGA) database. RRA method was applied to identify differentially expressed MAGs. A total of 192 significantly robust MAGs were determined among seven GEO datasets. MAGs were initially selected through the Lasso Cox regression analysis and 6 MAGs were included to construct a prognostic signature model. Transcriptome profile, patient prognosis, correlation between the risk score and clinicopathological features, immune cell infiltration characteristics, immunotherapy sensitivity and chemotherapy sensitivity differed between low- and high-risk groups after grouping according to median risk score. The reliability and applicability of the signature were further validated in the GSE31210, GSE50081 and GSE68465 cohort. CMap predicted 62 small molecule drugs on the base of the prognostic MAGs. Targeted drug staurosporine had hydrogen bonding with Gln-172 of SLC2A1, which is one of MAGs. Staurosporine could inhibit cell migration in A549 and H1299. We further verified mRNA and protein expression of 6 MAGs in A549 and H1299. The signature can serve as a promising prognostic tool and may provide a novel personalized therapeutic strategy for LUAD patients.

Keywords:  candidate drugs; lung adenocarcinoma; metastasis; prognostic; signature

DOI:  https://doi.org/10.18632/aging.204169
Sci Rep. 2022 Jul 14. 12(1): 12059

Clustering analysis and prognostic signature of lung adenocarcinoma based on the tumor microenvironment.

Qingqing Shan, Yifan Zhang, Zongan Liang.

Because of immunotherapy failure in lung adenocarcinoma, we have tried to find new potential biomarkers for differentiating different tumor subtypes and predicting prognosis. We identified two subtypes based on tumor microenvironment-related genes in this study. We used seven methods to analyze the immune cell infiltration between subgroups. Further analysis of tumor mutation load and immune checkpoint expression among different subgroups was performed. The least absolute shrinkage and selection operator Cox regression was applied for further selection. The selected genes were used to construct a prognostic 14-gene signature for LUAD. Next, a survival analysis and time-dependent receiver operating characteristics were performed to verify and evaluate the model. Gene set enrichment analyses and immune analysis in risk groups was also performed. According to the expression of genes related to the tumor microenvironment, lung adenocarcinoma can be divided into cold tumors and hot tumors. The signature we built was able to predict prognosis more accurately than previously known models. The signature-based tumor microenvironment provides further insight into the prediction of lung adenocarcinoma prognosis and may guide individualized treatment.

DOI: https://doi.org/10.1038/s41598-022-15971-4
Cancer Commun (Lond). 2022 Jul 11.

KRAS-G12D mutation drives immune suppression and the primary resistance of anti-PD-1/PD-L1 immunotherapy in non-small cell lung cancer.

Chengming Liu, Sufei Zheng, Zhanyu Wang, Sihui Wang, Xinfeng Wang, Lu Yang, Haiyan Xu, Zheng Cao, Xiaoli Feng, Qi Xue, Yan Wang, Nan Sun, Jie He.

   BACKGROUND: Although immune checkpoint inhibitors (ICIs) against programmed cell death protein 1 (PD-1) and its ligand PD-L1 have demonstrated potency towards treating patients with non-small cell lung carcinoma (NSCLC), the potential association between Kirsten rat sarcoma viral oncogene homolog (KRAS) oncogene substitutions and the efficacy of ICIs remains unclear. In this study, we aimed to find point mutations in the KRAS gene resistant to ICIs and elucidate resistance mechanism.
METHODS: The association between KRAS variant status and the efficacy of ICIs was explored with a clinical cohort (n = 74), and confirmed with a mouse model. In addition, the tumor immune microenvironment (TIME) of KRAS-mutant NSCLC, such as CD8+ tumor-infiltrating lymphocytes (TILs) and PD-L1 level, was investigated. Cell lines expressing classic KRAS substitutions were used to explore signaling pathway activation involved in the formation of TIME. Furthermore, interventions that improved TIME were developed to increase responsiveness to ICIs.
RESULTS: We observed the inferior efficacy of ICIs in KRAS-G12D-mutant NSCLC. Based upon transcriptome data and immunostaining results from KRAS-mutant NSCLC, KRAS-G12D point mutation negatively correlated with PD-L1 level and secretion of chemokines CXCL10/CXCL11 that led to a decrease in CD8+ TILs, which in turn yielded an immunosuppressive TIME. The analysis of cell lines overexpressing classic KRAS substitutions further revealed that KRAS-G12D mutation suppressed PD-L1 level via the P70S6K/PI3K/AKT axis and reduced CXCL10/CXCL11 levels by down-regulating high mobility group protein A2 (HMGA2) level. Notably, paclitaxel, a chemotherapeutic agent, upregulated HMGA2 level, and in turn, stimulated the secretion of CXCL10/CXCL11. Moreover, PD-L1 blockade combined with paclitaxel significantly suppressed tumor growth compared with PD-L1 inhibitor monotherapy in a mouse model with KRAS-G12D-mutant lung adenocarcinoma. Further analyses revealed that the combined treatment significantly enhanced the recruitment of CD8+ TILs via the up-regulation of CXCL10/CXCL11 levels. Results of clinical study also revealed the superior efficacy of chemo-immunotherapy in patients with KRAS-G12D-mutant NSCLC compared with ICI monotherapy.
CONCLUSIONS: Our study elucidated the molecular mechanism by which KRAS-G12D mutation drives immunosuppression and enhances resistance of ICIs in NSCLC. Importantly, our findings demonstrate that ICIs in combination with chemotherapy may be more effective in patients with KRAS-G12D-mutant NSCLC.

Keywords:  KRAS-G12D; PD-L1; chemo-immunotherapy; immunotherapy; non-small cell lung carcinoma; tumor-infiltrating lymphocyte

DOI:  https://doi.org/10.1002/cac2.12327
Int Immunopharmacol. 2022 Jul 09. pii: S1567-5769(22)00438-6. [Epub ahead of print]110 108954

High expression of PTGES3 is an independent predictive poor prognostic biomarker and correlates with immune infiltrates in lung adenocarcinoma.

Pengxiang Gao, Kang Zou, Li Xiao, Hongxia Zhou, Xinping Xu, Zhenguo Zeng, Wei Zhang.

   BACKGROUND: Immune-infiltration was positively relationship with overall survival in lung adenocarcinoma (LUAD). Nevertheless, the potential clinical value of PTGES3, especially in terms of prognosis and tumor immune-infiltration in LUAD had not been fully elucidated.
METHODS: Original data available from TCGA and GEO databases and integrated via R3.6.3. Kaplan-Meier and Cox regression methods were used to examine the effect of PTGES3 expression in overall survival, and nomogram was performed to illustrate the correlation between the PTGES3 expression and the risk of LUAD. The associate between PTGES3 and cancer immune characteristics were analyzed via the TISIDB databases. Western blot and RT-qPCR were used to analyze PTGES3 expression in the clinical lung adenocarcinoma tissue samples or non-small cell lung cancer cell lines.
RESULTS: PTGES3 mRNA and protein expression were significantly elevated in LUAD compared with normal lung tissues. Up-regulated PTGES3 was significantly associated with pathologic stage and TM stage. Kaplan-Meier survival analysis and subgroup analysis showed that up-regulated PTGES3 was associated with a worse overall survival of LUAD (HR = 1.71 (1.27-2.31), p < 0.001). Multivariate Cox analysis showed that high PTGES3 expression was an independent factor affecting overall survival (HR = 1.64 (1.14-2.37), p < 0.001). GO and KEGG analysis revealed that the cell cycle, regulation of DNA replication, and regulation of innate immune response were enriched. A positive correlation between PTGES3 expression and immune infiltrating levels of Th2 cells was found.
CONCLUSION: PTGES3 may play an important role in the cell cycle and as an independent predictive prognostic biomarker correlates with immune infiltrates in lung adenocarcinoma.

Keywords:  Biomarker; Cell cycle; Immune infiltrate; Lung adenocarcinoma (LUAD); Prognosis; Prostaglandin E synthase enzyme3 (PTGES3)

DOI:  https://doi.org/10.1016/j.intimp.2022.108954
J Biochem Mol Toxicol. 2022 Jul 13. e23166

Identification of Grb2-associated binding protein 3 expression to predict clinical outcomes and immunotherapeutic responses in lung adenocarcinoma.

Ning Wang, Xue Zhou, Xue Wang, Xiaowei Zhu.

  With the deepening research on tumor microenvironment (TME), immunotherapy has been deemed to be one of the major breakthroughs for cancer therapy. Nevertheless, only some patients respond well to this treatment. It is vital to explore predictive biomarkers for clinical benefit of immunotherapy. Grb2-associated binding protein 3 (GAB3) exerts essential biological functions in ovarian cancer and colorectal cancer. The potential role of GAB3 in lung adenocarcinoma (LUAD) has not been fully elucidated. RNA-sequencing data, genetic mutation data, and matched clinical data were obtained from the cancer genome atlas (TCGA) databases, then underwent gene expression, prognosis, enrichment, TME, immune checkpoint blockade (ICB) response analyses utilizing R packages. The mRNA expression level of GAB3 was dramatically decreased in LUAD, and the prognostic analysis indicated that the patients with low GAB3 expression performed unsatisfactory clinical outcomes. In addition, differentially expressed genes (DEGs) and subsequent functional enrichment analysis demonstrated that GAB3 was primarily connected with T cell activation and immune response. Finally, GAB3 expression positively correlated with immune infiltrates and immune checkpoint genes, and therapeutic effect of ICB. In summary, our study comprehensively uncovers that GAB3 may function as a promising biomarker to predict clinical outcomes and immunotherapeutic responses in LUAD patients.

Keywords:  GAB3; immune infiltrates; immunotherapy; lung adenocarcinoma; prognosis

DOI:  https://doi.org/10.1002/jbt.23166
Transl Lung Cancer Res. 2022 Jun;11(6): 1089-1107

Targeting STT3A produces an anti-tumor effect in lung adenocarcinoma by blocking the MAPK and PI3K/AKT signaling pathway.

Jiahan Cheng, Liang Xia, Xiaohu Hao, Fanyi Gan, Yuquan Bai, Chuanfen Zhang, Yonghong Mao, Yunke Zhu, Qiang Pu, Dong Won Park, Simona Tavolari, Jiandong Mei, Yaohui Chen, Senyi Deng, Lunxu Liu.

   Background: Glycosylation is crucial for the stability and biological functions of proteins. The aberrant glycosylation of critical proteins plays an important role in multiple cancers, including lung adenocarcinoma (LUAD). STT3 oligosaccharyltransferase complex catalytic subunit A (STT3A) is a major isoform of N-linked glycosyltransferase that catalyzes the glycosylation of various proteins. However, the functions of STT3A in LUAD are still unclear.
Methods: The expression profiles of STT3A were initially analyzed in public data sets and then validated by quantitative real-time polymerase chain reaction, Western blot and immunohistochemistry assays in clinical LUAD samples. The overall survival (OS) between patients with high and low STT3A expression was compared using a Kaplan-Meier curve with a log-rank analysis. STT3A was knocked-out using CRISPR/Cas9 and inhibited by NGI-1. Cell Counting Kit-8, colony formation assay, wound-healing, transwell assay, and flow cytometry were performed to assess the cellular functions of STT3A in vitro. A mice xenograft model was established to investigate the effects of STT3A on tumor growth in vivo. Further, the downstream signaling pathways of STT3A were screened by mass spectrometry with a bioinformatics analysis, and the activation of the target pathways were subsequently validated by Western blot.
Results: The expression of STT3A was frequently upregulated in LUAD tissues than normal lung tissues. The high expression of STT3A was significantly associated with poor OS in LUAD patients. The knockout or inhibition of STT3A suppressed proliferation, migration, and invasion, and arrested the cell cycle of LUAD cell lines in vitro. Similarly, the knockout or inhibition of STT3A suppressed tumor growth in vivo. In terms of molecular mechanism, STT3A may promote LUAD progression by activating the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase and protein kinase B (PI3K/AKT) pathways and regulating the epithelial-mesenchymal transition.
Conclusions: STT3A promotes LUAD progression via the MAPK and PI3K/AKT signaling pathways and could serve as a novel prognostic biomarker and potential therapeutic target for LUAD patients.

Keywords:  MAPK/ERK pathway; STT3 oligosaccharyltransferase complex catalytic subunit A (STT3A); glycosylation; lung adenocarcinoma; phosphatidylinositol-3-kinase and protein kinase B pathway (PI3K/AKT pathway)

DOI:  https://doi.org/10.21037/tlcr-22-396