bims-meluca 2022-05-22 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2022–05–22
eight 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

Glucose-Restricted Diet Regulates the Tumor Immune Microenvironment and Prevents Tumor Growth in Lung Adenocarcinoma.
The integrated stress response in the induction of mutant KRAS lung carcinogenesis: Mechanistic insights and therapeutic implications.
Response to immunotherapy in KRAS G12C mutated NSCLC: a single-centre retrospective observational study.
Clinical significance of plasma-free amino acids and tryptophan metabolites in patients with non-small cell lung cancer receiving PD-1 inhibitor: a pilot cohort study for developing a prognostic multivariate model.
The effect of sarcopenia on erlotinib therapy in patients with metastatic lung adenocarcinoma.
Suppression of nuclear GSK3 signaling promotes serine/one-carbon metabolism and confers metabolic vulnerability in lung cancer cells.
CDC25C as a Predictive Biomarker for Immune Checkpoint Inhibitors in Patients With Lung Adenocarcinoma.
Overexpressed p-S6 associates with lymph node metastasis and predicts poor prognosis in non-small cell lung cancer.

Front Oncol. 2022 ;12 873293

Glucose-Restricted Diet Regulates the Tumor Immune Microenvironment and Prevents Tumor Growth in Lung Adenocarcinoma.

Alexander Gähler, Denis I Trufa, Mircea T Chiriac, Patrick Tausche, Katja Hohenberger, Ann-Kathrin Brunst, Manfred Rauh, Carol I Geppert, Ralf J Rieker, Susanne Krammer, Anna Leberle, Markus F Neurath, Horia Sirbu, Arndt Hartmann, Susetta Finotto.

   Background: Lung cancer is the second common cancer type in western countries and has a high mortality. During the development and progression of the tumor, the nutrients in its environment play a central role. The tumor cells depend crucially on glucose metabolism and uptake. Tumor cell metabolism is dominated by the Warburg effect, where tumor cells produce large amounts of lactate from pyruvate under aerobic conditions. We thus reasoned that, reducing carbohydrates in the diet might support anti-tumoral effects of current immunotherapy and additionally target tumor immune escape.
Objectives: The link between reducing carbohydrates to improve current immunotherapy is not clear. We thus aimed at analyzing the effects of different glucose levels on the tumor development, progression and the anti-tumoral immune response.
Methods: We correlated the clinical parameters of our LUAD cohort with different metabolic markers. Additionally, we performed cell culture experiments with A549 tumor cell line under different glucose levels. Lastly, we investigated the effect of low and high carbohydrate diet in an experimental murine model of lung cancer on the tumor progression and different immune subsets.
Results: Here we found a positive correlation between the body mass index (BMI), blood glucose levels, reduced overall survival (OS) and the expression of Insulin-like growth factor-1 receptor (IGF1R) in the lung tumoral region of patients with lung adenocarcinoma (LUAD). Furthermore, increasing extracellular glucose induced IGF1R expression in A549 LUAD cells. Functional studies in a murine model of LUAD demonstrated that, glucose restricted diet resulted in decreased tumor load in vivo. This finding was associated with increased presence of lung infiltrating cytotoxic CD8+ T effector memory (TEM), tissue resident memory T (TRM) and natural killer cells as well as reduced IGFR mRNA expression, suggesting that glucose restriction regulates lung immunity in the tumor microenvironment.
Conclusions: These results indicate that, glucose restricted diet improves lung immune responses of the host and suppresses tumor growth in experimental lung adenocarcinoma. As glucose levels in LUAD patients were negatively correlated to postoperative survival rates, glucose-restricted diet emerges as therapeutic avenue for patients with LUAD.

Keywords:  A549; BMI; IGFR; Immunotherapy; NSCLC; glucose

DOI:  https://doi.org/10.3389/fonc.2022.873293
Bioessays. 2022 May 19. e2200026

The integrated stress response in the induction of mutant KRAS lung carcinogenesis: Mechanistic insights and therapeutic implications.

Antonis E Koromilas.

  The integrated stress response (ISR) is a key determinant of tumorigenesis in response to oncogenic forms of stress like genotoxic, proteotoxic and metabolic stress. ISR relies on the phosphorylation of the translation initiation factor eIF2 to promote the translational and transcriptional reprogramming of gene expression in stressed cells. While ISR promotes tumor survival under stress, its hyperactivation above a level of tolerance can also cause tumor death. The tumorigenic function of ISR has been recently demonstrated for lung adenocarcinomas (LUAD) with KRAS mutations. ISR mediates the translational repression of the dual-specificity phosphatase DUSP6 to stimulate ERK activity and LUAD growth. The significance of this finding is highlighted by the strong anti-tumor responses of ISR inhibitors in pre-clinical LUAD models. Elucidation of the mechanisms of ISR action in LUAD progression via cell-autonomous and immune regulatory mechanisms will provide a better understanding of its tumorigenic role to fully exploit its therapeutic potential in the treatment of a deadly form of cancer.

Keywords:  KRAS oncogene; cancer therapeutics; lung adenocarcinoma; mRNA translation; oncogenic stress; transgenic mouse; translation initiation factor eIF2

DOI:  https://doi.org/10.1002/bies.202200026
Oncotarget. 2022 ;13 686-693

Response to immunotherapy in KRAS G12C mutated NSCLC: a single-centre retrospective observational study.

Carolina Sciortino, Valentina Viglialoro, Massimo Nucci, Mariam Grazia Polito, Enrico Cortesi, Alain Gelibter, Paola Gazzaniga, Chiara Nicolazzo, Marco Siringo, Salvatore Caponnetto.

   BACKGROUND: Non-small cell lung cancer is the leading cause of cancer death worldwide. New strategies in molecular therapies are being explored to detect and target genetic mutations in NSCLC. Therefore, it is also important to understand the interaction between these mutations and other therapies. This study focuses on possible correlations between the KRAS-G12C mutation and response of patients treated with immunotherapy.
METHODS: Twenty-two patients with stage IV NSCLC undergoing immunotherapy were divided into two groups treated with first- and second-line therapy, respectively. KRAS-G12C mutation was detected by liquid biopsy Idylla KRAS assay.
RESULTS: In first-line treated patients, there was no significant increase in PFS in patients with the KRAS mutation (20 months versus 14.5 months, HR = 1.31; CI 95% = 0.25-6.71; p value = 0.76) and no difference in OS (OS = 21 months, HR = 1; CI 95% = 0.17-6.2; p value > 0.99). In the second group, KRAS G12C mutated patients had a median PFS of 23 months compared with a median PFS of only 5 months among nonmutated patients (HR = 3.28; CI 95% = 0.86-12.5; p value = 0.03).
CONCLUSION: The results of this study do not reveal a clear correlation between mutation and response to immunotherapy. The mechanism regulating immune system activity in the tumor microenvironment remains unclear.

Keywords:  KRAS G12C mutation; NSCLC; immunotherapy; liquid biopsy

DOI:  https://doi.org/10.18632/oncotarget.28230
J Immunother Cancer. 2022 May;pii: e004420. [Epub ahead of print]10(5):

Clinical significance of plasma-free amino acids and tryptophan metabolites in patients with non-small cell lung cancer receiving PD-1 inhibitor: a pilot cohort study for developing a prognostic multivariate model.

Koichi Azuma, Huihui Xiang, Tomoyuki Tagami, Rika Kasajima, Yumiko Kato, Sachise Karakawa, Shinya Kikuchi, Akira Imaizumi, Norikazu Matsuo, Hidenobu Ishii, Takaaki Tokito, Akihiko Kawahara, Kenta Murotani, Tetsuro Sasada, Yohei Miyagi, Tomoaki Hoshino.

   BACKGROUND: Amino acid metabolism is essential for tumor cell proliferation and regulation of immune cell function. However, the clinical significance of free amino acids (plasma-free amino acids (PFAAs)) and tryptophan-related metabolites in plasma has not been fully understood in patients with non-small cell lung cancer (NSCLC) who receive immune checkpoint inhibitors.
METHODS: We conducted a single cohort observational study. Peripheral blood samples were collected from 53 patients with NSCLC before treatment with PD-1 (Programmed cell death-1) inhibitors. The plasma concentrations of 21 PFAAs, 14 metabolites, and neopterin were measured by liquid chromatography-mass spectrometry. Using Cox hazard analysis with these variables, a multivariate model was established to stratify patient overall survival (OS). Gene expression in peripheral blood mononuclear cells (PBMCs) was compared between the high-risk and low-risk patients by this multivariate model.
RESULTS: On Cox proportional hazard analysis, higher concentrations of seven PFAAs (glycine, histidine, threonine, alanine, citrulline, arginine, and tryptophan) as well as lower concentrations of three metabolites (3h-kynurenine, anthranilic acid, and quinolinic acid) and neopterin in plasma were significantly correlated with better OS (p<0.05). In particular, the multivariate model, composed of a combination of serine, glycine, arginine, and quinolinic acid, could most efficiently stratify patient OS (concordance index=0.775, HR=3.23, 95% CI 2.04 to 5.26). From the transcriptome analysis in PBMCs, this multivariate model was significantly correlated with the gene signatures related to immune responses, such as CD8 T-cell activation/proliferation and proinflammatory immune responses, and 12 amino acid-related genes were differentially expressed between the high-risk and low-risk groups.
CONCLUSIONS: The multivariate model with PFAAs and metabolites in plasma might be useful for stratifying patients who will benefit from PD-1 inhibitors.

Keywords:  Immunotherapy; Lung Neoplasms; Programmed Cell Death 1 Receptor; Translational Medical Research; Tumor Biomarkers

DOI:  https://doi.org/10.1136/jitc-2021-004420
Bosn J Basic Med Sci. 2022 May 14.

The effect of sarcopenia on erlotinib therapy in patients with metastatic lung adenocarcinoma.

Atakan Topcu, Akin Ozturk, Ismail Yurtsever, Mehmet Besiroglu, Ayse Irem Yasin, Haci Mehmet Turk, Mesut Seker.

Erlotinib, a tyrosine kinase inhibitor, has been shown to improve the survival of patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer. Sarcopenia is a status with increasing importance in lung cancer, and it may predict a poor prognosis. We aimed to evaluate the impact of sarcopenia on erlotinib therapy and prognosis in patients with EGFR-mutated (exon 19 or 21 L858R) metastatic lung adenocarcinoma. Sarcopenia was defined as skeletal muscle index ≤39 cm2/m2 for women and ≤55 cm2/m2 for men. The patient characteristics, inflammation parameters, clinical and survival outcomes of the erlotinib therapy were examined according to sarcopenia status. We also analyzed the erlotinib treatment-related toxicity. Seventy-two patients were included in our retrospective study, and the mean age of the patients was 63.7 years. A total of 39 (54.2%) patients were diagnosed with sarcopenia. Patients with sarcopenia had a poor prognosis and had a shorter median progression-free survival (PFS) than patients without sarcopenia (10.5 months vs. 21.8 months, p=0.002). Sarcopenia (HR 2.08) and C-reactive protein > 6.5 mg/L (HR 2.57) were determined as independent poor prognostic factors for PFS of erlotinib therapy. Treatment-related toxicity occurred in 34.7% of patients treated with erlotinib, and sarcopenia did not significantly affect treatment-related toxicity. We also found that sarcopenia significantly affected the response to erlotinib. The expected survival outcomes may be low when erlotinib therapy is used in patients with sarcopenia and metastatic lung adenocarcinoma. This study showed that survival and clinical outcomes could be better predicted by detecting sarcopenia in patients with lung cancer using erlotinib.

DOI: https://doi.org/10.17305/bjbms.2022.7147
Sci Adv. 2022 May 20. 8(20): eabm8786

Suppression of nuclear GSK3 signaling promotes serine/one-carbon metabolism and confers metabolic vulnerability in lung cancer cells.

Long He, Jennifer Endress, Sungyun Cho, Zhongchi Li, Yuxiang Zheng, John M Asara, John Blenis.

Serine/one-carbon metabolism provides critical resources for nucleotide biosynthesis and epigenetic maintenance and is thus necessary in cancer cell growth, although the detailed regulatory mechanisms remain unclear. We uncover a critical role of glycogen synthase kinase 3 (GSK3) in regulating the expression of serine/one-carbon metabolic enzymes. Nuclear enrichment of GSK3 significantly suppresses genes that mediate de novo serine synthesis, including PHGDH, PSAT1, PSPH, and one-carbon metabolism, including SHMT2 and MTHFD2. FRAT1 promotes nuclear exclusion of GSK3, enhances serine/one-carbon metabolism, and, as a result, confers cell vulnerability to inhibitors that target this metabolic process such as SHIN1, a specific SHMT1/2 inhibitor. Furthermore, pharmacological or genetic suppression of GSK3 promotes serine/one-carbon metabolism and exhibits a significant synergistic effect in combination with SHIN1 in suppressing cancer cell proliferation in cultured cells and in vivo. Our observations indicate that inhibition of nuclear GSK3 signaling creates a vulnerability, which results in enhanced efficacy of serine/one-carbon metabolism inhibitors for the treatment of cancer.

DOI: https://doi.org/10.1126/sciadv.abm8786
Front Oncol. 2022 ;12 867788

CDC25C as a Predictive Biomarker for Immune Checkpoint Inhibitors in Patients With Lung Adenocarcinoma.

Wengang Zhang, Xiaoling Shang, Fei Yang, Wenfei Han, Handai Xia, Ni Liu, Yanguo Liu, Xiuwen Wang.

  The application of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer has significantly improved patient survival. However, most patients fail to respond to ICIs or develop drug resistance during treatment. Therefore, novel biomarkers are needed to predict the efficacy of ICIs or provide clues on how to overcome drug resistance. Here, it was revealed that cell division cycle 25C (CDC25C) expression was upregulated in lung adenocarcinoma (LUAD) compared to that of normal lung tissue in multiple databases. This was further verified by q-PCR. Furthermore, higher CDC25C expression was associated with shorter overall survival and worse pathological stage. Most importantly, a higher CDC25C expression was associated with shorter progression-free survival in LUAD patients treated with nivolumab, suggesting the role of the cell cycle in immunotherapy. In addition, CDC25C expression was significantly associated with immune cell infiltration and immune-related signatures in the LUAD tumor microenvironment. Moreover, CDC25C was differentially expressed and correlated with overall survival in multiple tumors, indicating that CDC25C is a broad-spectrum biomarker. Taken together, our study demonstrates that CDC25C is a prognostic biomarker for LUAD patients, especially for patients treated with ICIs. Our study also provides strong evidence for the role of the cell cycle in ICIs therapy and tumor microenvironment.

Keywords:  CDC25C; biomarker; immune checkpoint inhibitors; lung adenocarcinoma; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2022.867788
BMC Cancer. 2022 May 20. 22(1): 564

Overexpressed p-S6 associates with lymph node metastasis and predicts poor prognosis in non-small cell lung cancer.

Yaoxiang Tang, Jiadi Luo, Ying Zhou, Hongjing Zang, Yang Yang, Sile Liu, Hongmei Zheng, Jian Ma, Songqing Fan, Qiuyuan Wen.

   BACKGROUND: Ribosomal protein S6 (S6), a downstream effect media of the AKT/mTOR pathway, not only is a part of 40S small subunit of eukaryotic ribosome, but also involves in protein synthesis and cell proliferation during cancer development.
METHODS: In present study, we explore the association between phosphorylated S6 (p-S6) protein expression and clinicopathological features as well as prognostic implications in NSCLC. P-S6 was detected in tissue microarrays (TMAs) containing 350 NSCLC, 53 non-cancerous lung tissues (Non-CLT), and 88 cases of matched metastatic lymph node lesions via immunohistochemistry (IHC). Transwell assays and wound healing assay were used to assess the effects of p-S6 inhibition on NSCLC cell metastasis.
RESULTS: The p-S6 expression in NSCLC was more evident than that in Non-CLT (p < 0.05). Compared to NSCLC patients who have no lymph node metastasis (LNM), those with LNM had higher p-S6 expression (p = 0.001). Regardless of lung squamous cell carcinoma (SCC) or adenocarcinoma (ADC), p-S6 was increased obviously in metastatic lymph nodes compared with matched primary cancers (p = 0.001, p = 0.022, respectively). Inhibition of p-S6 decreased the metastasis ability of NSCLC cells. In addition, p-S6 was an independent predicted marker for LNM in patients with NSCLC (p < 0.001). According to survival analysis, patients with highly expressed p-S6 had a lower survival rate compared with that with lower expression (p = 0.013). P-S6 is an unfavorable independent prognostic factor for NSCLC patients (p = 0.011).
CONCLUSION: Increased expression of p-S6 is not only a novel predictive biomarker of LNM but also poor prognosis in NSCLC.

Keywords:  Lymph node metastasis; Non-small cell lung cancer; P-S6; Prognosis

DOI:  https://doi.org/10.1186/s12885-022-09664-4