bims-meluca 2022-02-06 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2022–02–06
six 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

High expression of monocarboxylate transporter 4 (MCT 4), but not MCT 1, predicts poor prognosis in patients with non-small cell lung cancer.
NRF2: KEAPing Tumors Protected.
Inhibition of stearoyl-CoA desaturase 1 potentiates anti-tumor activity of amodiaquine in non-small cell lung cancer.
Association between BRAF mutant classification and the efficacy of pemetrexed-based chemotherapy in Chinese advanced non-small cell lung cancer patients: a multicenter retrospective study.
Stratification of lung squamous cell carcinoma based on ferroptosis regulators: Potential for new therapeutic strategies involving ferroptosis induction.
Pyruvate kinase M2 is a marker of poor prognosis in lung adenocarcinoma but not lung squamous cell carcinoma.

Transl Cancer Res. 2021 Mar;10(3): 1336-1345

High expression of monocarboxylate transporter 4 (MCT 4), but not MCT 1, predicts poor prognosis in patients with non-small cell lung cancer.

Ying-Hui Tong, Xiao-Ping Hu, Xue-Ping Xiang, Luo Fang.

   Background: The monocarboxylate transporter (MCT) family especially MCT1 and MCT4 have been recognized to play an important role in lactate transport, a key glycolytic product. The expression of MCT1 and MCT4 expression was previously found to be related to poor outcome in various cancer types. In this study, we investigated the expression status of MCT1 and MCT4 and their relationship with prognosis in non-small cell lung cancer (NSCLC).
Methods: Expression of MCT4 and MCT1 in NSCLC tumor and adjacent lung tissues were detected by immunohistochemistry. Kaplan-Meier plots were used to evaluate two proteins' prognostic role, and the log-rank test obtained the P value. For multivariate analysis, the Cox proportional-hazards regression method was performed.
Results: High MCT4 and MCT1 expression was observed in cancer cells, with a rate of 45% for MCT4 versus 15% for MCT1 among all NSCLC patients. High expression of MCT4, and not MCT1, was associated with worse overall survival (OS) [hazard ratio (HR) =1.96 (1.06-3.75), P=0.032] and progression-free survival (PFS) [HR =1.72 (1.05-2.93), P=0.032] in NSCLC patients. In our multivariate analysis, advanced cancer stage and high MCT4 level were identified as independent predictive indicators for both PFS [HR(MCT4) =1.888 (1.114-3.199), P=0.018 and OS [HR (MCT4) =2.421 (1.271-4.610), P=0.007]. Subgroup and interaction analyses were also performed in different clinical characteristic groups and no significant differences were observed.
Conclusions: High MCT4 expression is a predictive marker for worse outcome in NSCLC patients.

Keywords:  Monocarboxylate transporter 1 (MCT1); monocarboxylate transporter 4 (MCT4); non-small cell lung cancer (NSCLC); prognosis

DOI:  https://doi.org/10.21037/tcr-20-3117
Cancer Discov. 2022 Jan 31.

NRF2: KEAPing Tumors Protected.

Ray Pillai, Makiko Hayashi, Anastasia-Maria Zavitsanou, Thales Papagiannakopoulos.

The Kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway plays a physiologic protective role against xenobiotics and reactive oxygen species. However, activation of NRF2 provides a powerful selective advantage for tumors by rewiring metabolism to enhance proliferation, suppress various forms of stress, and promote immune evasion. Genetic, epigenetic, and posttranslational alterations that activate the KEAP1/NRF2 pathway are found in multiple solid tumors. Emerging clinical data highlight that alterations in this pathway result in resistance to multiple therapies. Here, we provide an overview of how dysregulation of the KEAP1/NRF2 pathway in cancer contributes to several hallmarks of cancer that promote tumorigenesis and lead to treatment resistance. SIGNIFICANCE: Alterations in the KEAP1/NRF2 pathway are found in multiple cancer types. Activation of NRF2 leads to metabolic rewiring of tumors that promote tumor initiation and progression. Here we present the known alterations that lead to NRF2 activation in cancer, the mechanisms in which NRF2 activation promotes tumors, and the therapeutic implications of NRF2 activation.

DOI: https://doi.org/10.1158/2159-8290.CD-21-0922
Biol Pharm Bull. 2022 Feb 03.

Inhibition of stearoyl-CoA desaturase 1 potentiates anti-tumor activity of amodiaquine in non-small cell lung cancer.

Xiaolei Hu, Jiangning Xiang, Yibo Li, Yan Xia, Siyuan Xu, Xiaoge Gao, Shuxi Qiao.

  Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer related death with few therapeutic treatment options. Under adverse tumor microenvironment, autophagy is an important mechanism of metabolic adaptations to sustain the survival and proliferation of tumor cells. Therefore, targeting autophagic activity represents a promising opportunity for NSCLC treatment. Here, we found that amodiaquine (AQ) increased autophagosome numbers and LC3BII and p62 at protein levels in A549 lung cancer cells suggesting the blockade of autophagic flux by AQ. To identify the key metabolic vulnerability associated with autophagy inhibition by AQ treatment, we then performed transcriptomics analysis in the presence or absence of AQ in A549 lung cancer cells and found stearoyl-CoA desaturase 1 (SCD) 1 was one of the most highly upregulated with AQ exposure. The induction of SCD1 by AQ exposure at both protein and mRNA level suggests that SCD1 could represent a potential therapeutic target of AQ treatment. Treatment of AQ in combination with SCD1 inhibition by A939572 demonstrated robust synergistic anti-cancer efficacy in cell proliferation assay and a lung cancer mouse xenograft model. Taken together, our study identified SCD1 could be a new therapeutic target upon autophagy inhibition by AQ exposure. Combinational treatment of autophagy inhibition and SCD1 inhibition achieves synergistic anti-tumor effect both in vitro and in vivo. This combinational approach could be a promising strategy for NSCLC treatment.

Keywords:  amodiaquine; autophagy; combinational therapy; non-small cell lung cancer; stearoyl-CoA desaturase 1

DOI:  https://doi.org/10.1248/bpb.b21-00843
Transl Cancer Res. 2020 Oct;9(10): 6039-6049

Association between BRAF mutant classification and the efficacy of pemetrexed-based chemotherapy in Chinese advanced non-small cell lung cancer patients: a multicenter retrospective study.

Lei Lei, Wen-Xian Wang, You-Cai Zhu, Xing-Xiang Pu, Yong Fang, Hong Wang, Wu Zhuang, Yin-Bin Zhang, Li-Ping Wang, Chun-Wei Xu, Mei-Yu Fang.

   Background: BRAF mutation plays a rare but aggressive oncogenic role in non-small cell lung cancer (NSCLC) patients. The controversy of first-line chemotherapy in patients with different BRAF mutations exists. Here, we identified 41 stage IIIB/IV NSCLC patients with BRAF mutation from 3,669 NSCLC patients by next-generation sequencing (NGS) testing of ctDNA in plasma or tumor tissues.
Methods: Kaplan-Meier survival curves were used to compare the prognostic difference of progression-free survival (PFS) and overall survival (OS) in different classes of BRAF mutations. Multivariate Cox proportional-hazards regression was used to determine the hazard ratio (HR) of different prognostic factors in survival.
Results: A total of 40 stage IIIB/IV NSCLC patients with BRAF mutation were further divided into four groups according to the updated functional classification of BRAF mutations, 56.1% (23/41) of class 1, 12.2% (5/41) of class 2, 12.2% (5/41) of class 3 and 19.5% (8/41) of others. The median PFS of patients after first-line pemetrexed-based chemotherapy was longer than other regimens of chemotherapy (7.0 vs. 4.0 months, P<0.001). The patients with class 1 BRAF mutation treated with pemetrexed-based first-line chemotherapy had a better OS than other regimens of chemotherapy (30 vs. 22 months, P<0.001). A significant improvement of OS was observed in patients with class 1 BRAF mutation than other groups (25 vs. 12, 15 and 14 months, P<0.0001). Multivariate analysis showed that first-line pemetrexed-based chemotherapy was associated with better PFS and OS (HR =0.16 and 0.31, respectively; P<0.001 and 0.02, respectively), as well as improved OS in patients with class 1 BRAF mutation than other classes (HR =2.15, P<0.001).
Conclusions: Pemetrexed-based regimen could be considered as first-line chemotherapy in advanced NSCLC patients with BRAF mutants when target therapy is unavailable, especially in patients harboring class 1 mutations compared with other classes.

Keywords:  BRAF mutation; chemotherapy; non-small cell lung cancer (NSCLC); pemetrexed

DOI:  https://doi.org/10.21037/tcr-20-480
Lung Cancer. 2022 Jan 24. pii: S0169-5002(22)00024-1. [Epub ahead of print]165 82-90

Stratification of lung squamous cell carcinoma based on ferroptosis regulators: Potential for new therapeutic strategies involving ferroptosis induction.

Ayaka Asakawa, Genji Kawade, Morito Kurata, Sho Fukuda, Iichiroh Onishi, Yuko Kinowaki, Sachiko Ishibashi, Masumi Ikeda, Shiori Watabe, Masashi Kobayashi, Hironori Ishibashi, Kenichi Okubo, Masanobu Kitagawa, Kouhei Yamamoto.

   OBJECTIVES: Lung squamous cell carcinoma (LSCC) exhibits poor response to treatment compared with other lung cancer subtypes, resulting in worse prognosis. Therefore, new therapeutic strategies are required for advanced LSCC. Ferroptosis is a recently discovered nonapoptotic cell death caused by intracellular lipid peroxidation that can bring about effective cell death in cancer cells resistant to apoptosis. Hence, ferroptosis is a potential therapeutic strategy for refractory cancer.
MATERIALS AND METHODS: In this study, we performed clinicopathological and molecular analyses on tumor specimens from 270 patients with squamous cell lung cancer, focusing on the expression of glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1), which are known to be key regulators of ferroptosis, and the accumulation of 4-hydroxynoneral (4-HNE), a lipid peroxidation marker.
RESULTS: Immunohistochemistry revealed that patients with low 4-HNE accumulation and low levels of GPX4 or FSP1 had significantly worse prognoses than other patients (P = 0.001). This stratification was an independent prognostic predictor (P = 0.003). A dramatic cell death synergistic effect was observed on LSCC-derived LK-2 and EBC1 cells treated with GPX4 and FSP1 inhibitors. This effect was completely inhibited by treatment with the ferroptosis inhibitor. Notably, this was not the case in LK-2 cells treated with the apoptosis inhibitor, and in these cells, ferroptosis was induced.
CONCLUSION: Ferroptosis regulators GPX4 and FSP1 are associated with lung squamous cell cancer cancer's prognosis. We present the clinicopathological and molecular basis of novel therapeutic strategies for refractory LSCC.

Keywords:  Ferroptosis; Lipid peroxidation; Lung squamous cell carcinoma; Nonapoptotic cell death; Refractive cancer; Therapy

DOI:  https://doi.org/10.1016/j.lungcan.2022.01.012
Transl Cancer Res. 2020 May;9(5): 3293-3302

Pyruvate kinase M2 is a marker of poor prognosis in lung adenocarcinoma but not lung squamous cell carcinoma.

Junxia Zhang, Chengjuan Zhang, Xianghua Liu, Ning Sun, Caili Zhang, Ruiqin Li, Zhenqiang Zhang.

   Background: To explore the pyruvate kinase M2 (PKM2) expression profile as a prognostic marker of lung adenocarcinoma (LUAD) as well as lung squamous cell carcinoma (LUSC).
Methods: Retrospective bioinformatics analysis of data from the Cancer Genome Atlas-Lung Cancer dataset and the Human Protein Atlas was performed. PKM2 mRNA expression was monitored using the Kaplan-Meier Plotter online database. GraphPad Prism 6.0 and the SPSS 19.0 software package were used for statistical analysis.
Results: PKM2 expression was found to be significantly higher in both LUAD and LUSC than in normal controls. Although increased PKM2 expression in LUAD was correlated with poor overall survival (OS) [hazard ratio (HR): 2.128; 95% CI: 1.754-3.653; P<0.001], recurrence-free survival (RFS) (HR: 1.524; 95% CI: 1.069-2.499; P=0.0237), and progression-free survival (PFS) (HR: 2.18; 95% CI: 1.58-3; P<0.001), no such associations were found in LUSC.
Conclusions: PKM2 is a potential prognostic biomarker for LUAD but not for LUSC.

Keywords:  Pyruvate kinase M2 (PKM2); lung adenocarcinoma (LUAD); lung squamous cell carcinoma (LUSC); prognosis

DOI:  https://doi.org/10.21037/tcr.2020.04.23