bims-meluca 2022-07-24 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2022–07–24
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

Deacetylation of Glutaminase by HDAC4 contributes to Lung Cancer Tumorigenesis.
Targeting Glutamine Metabolism to Enhance Immunoprevention of EGFR-Driven Lung Cancer.
The strategic roles of four enzymes in the interconnection between metabolism and oncogene activation in non-small cell lung cancer: Therapeutic implications.
Activated amino acid response pathway generates apatinib resistance by reprograming glutamine metabolism in non-small-cell lung cancer.
Claudin 6 is associated with a short survival and a short recurrent free interval in non-small cell lung carcinoma.
LINE-1 promotes tumorigenicity and exacerbates tumor progression via stimulating metabolism reprogramming in non-small cell lung cancer.
Excess weight and anti-PD-1 immune checkpoint inhibitor's outcomes in non-small cell lung cancer.
Circulating L-Arginine predicts the survival of cancer patients treated with immune checkpoint inhibitors.

Int J Biol Sci. 2022 ;18(11): 4452-4465

Deacetylation of Glutaminase by HDAC4 contributes to Lung Cancer Tumorigenesis.

Tao Wang, Zhuo Lu, Tianyu Han, Yanan Wang, Mingxi Gan, Jian-Bin Wang.

  Inhibiting cancer metabolism via glutaminase (GAC) is a promising strategy to disrupt tumor progression. However, mechanism regarding GAC acetylation remains mostly unknown. In this study, we demonstrate that lysine acetylation is a vital post-translational modification that inhibits GAC activity in non-small cell lung cancer (NSCLC). We identify that Lys311 is the key acetylation site on GAC, which is deacetylated by HDAC4, a class II deacetylase. Lys311 acetylation stimulates the interaction between GAC and TRIM21, an E3 ubiquitin ligase of the tripartite motif (TRIM) family, therefore promoting GAC K63-linked ubiquitination and inhibiting GAC activity. Furthermore, GACK311Q mutation in A549 cells decreases cell proliferation and alleviates tumor malignancy. Our findings reveal a novel mechanism of GAC regulation by acetylation and ubiquitination that participates in non-small cell lung cancer tumorigenesis.

Keywords:  HDAC4; TRIM21; acetylation; glutaminase; non-small cell lung cancer

DOI:  https://doi.org/10.7150/ijbs.69882
Adv Sci (Weinh). 2022 Jul 21. e2105885

Targeting Glutamine Metabolism to Enhance Immunoprevention of EGFR-Driven Lung Cancer.

Mofei Huang, Donghai Xiong, Jing Pan, Qi Zhang, Shizuko Sei, Robert H Shoemaker, Ronald A Lubet, Luis M Montuenga, Yian Wang, Barbara S Slusher, Ming You.

  Lung cancer is the leading cause of cancer death worldwide. Vaccination against EGFR can be one of the venues to prevent lung cancer. Blocking glutamine metabolism has been shown to improve anticancer immunity. Here, the authors report that JHU083, an orally active glutamine antagonist prodrug designed to be preferentially activated in the tumor microenvironment, has potent anticancer effects on EGFR-driven mouse lung tumorigenesis. Lung tumor development is significantly suppressed when treatment with JHU083 is combined with an EGFR peptide vaccine (EVax) than either single treatment. Flow cytometry and single-cell RNA sequencing of the lung tumors reveal that JHU083 increases CD8+ T cell and CD4+ Th1 cell infiltration, while EVax elicits robust Th1 cell-mediated immune responses and protects mice against EGFRL858R mutation-driven lung tumorigenesis. JHU083 treatment decreases immune suppressive cells, including both monocytic- and granulocytic-myeloid-derived suppressor cells, regulatory T cells, and pro-tumor CD4+ Th17 cells in mouse models. Interestingly, Th1 cells are found to robustly upregulate oxidative metabolism and adopt a highly activated and memory-like phenotype upon glutamine inhibition. These results suggest that JHU083 is highly effective against EGFR-driven lung tumorigenesis and promotes an adaptive T cell-mediated tumor-specific immune response that enhances the efficacy of EVax.

Keywords:  JHU-083; epidermal growth factor receptor vaccines; glutamine metabolism; lung tumorigenesis; tumor immune microenvironment

DOI:  https://doi.org/10.1002/advs.202105885
Drug Resist Updat. 2022 Jul 06. pii: S1368-7646(22)00051-6. [Epub ahead of print]63 100852

The strategic roles of four enzymes in the interconnection between metabolism and oncogene activation in non-small cell lung cancer: Therapeutic implications.

Philippe Icard, Luca Simula, Ludovic Fournel, Karen Leroy, Audrey Lupo, Diane Damotte, Marie Christine Charpentier, Catherine Durdux, Mauro Loi, Olivier Schussler, Guillaume Chassagnon, Antoine Coquerel, Hubert Lincet, Vincent De Pauw, Marco Alifano.

  NSCLC is the leading cause of cancer mortality and represents a major challenge in cancer therapy. Intrinsic and acquired anticancer drug resistance are promoted by hypoxia and HIF-1α. Moreover, chemoresistance is sustained by the activation of key signaling pathways (such as RAS and its well-known downstream targets PI3K/AKT and MAPK) and several mutated oncogenes (including KRAS and EGFR among others). In this review, we highlight how these oncogenic factors are interconnected with cell metabolism (aerobic glycolysis, glutaminolysis and lipid synthesis). Also, we stress the key role of four metabolic enzymes (PFK1, dimeric-PKM2, GLS1 and ACLY), which promote the activation of these oncogenic pathways in a positive feedback loop. These four tenors orchestrating the coordination of metabolism and oncogenic pathways could be key druggable targets for specific inhibition. Since PFK1 appears as the first tenor of this orchestra, its inhibition (and/or that of its main activator PFK2/PFKFB3) could be an efficacious strategy against NSCLC. Citrate is a potent physiologic inhibitor of both PFK1 and PFKFB3, and NSCLC cells seem to maintain a low citrate level to sustain aerobic glycolysis and the PFK1/PI3K/EGFR axis. Awaiting the development of specific non-toxic inhibitors of PFK1 and PFK2/PFKFB3, we propose to test strategies increasing citrate levels in NSCLC tumors to disrupt this interconnection. This could be attempted by evaluating inhibitors of the citrate-consuming enzyme ACLY and/or by direct administration of citrate at high doses. In preclinical models, this "citrate strategy" efficiently inhibits PFK1/PFK2, HIF-1α, and IGFR/PI3K/AKT axes. It also blocks tumor growth in RAS-driven lung cancer models, reversing dedifferentiation, promoting T lymphocytes tumor infiltration, and increasing sensitivity to cytotoxic drugs.

Keywords:  ACLY; EGFR; GLS1; KRAS; NSCLC; PFK1; PI3K; PKM2

DOI:  https://doi.org/10.1016/j.drup.2022.100852
Cell Death Dis. 2022 Jul 21. 13(7): 636

Activated amino acid response pathway generates apatinib resistance by reprograming glutamine metabolism in non-small-cell lung cancer.

Xiaoshu Zhou, Rui Zhou, Xinrui Rao, Jiaxin Hong, Qianwen Li, Xiaohua Jie, Jian Wang, Yingzhuo Xu, Kuikui Zhu, Zhenyu Li, Gang Wu.

The efficacy of apatinib has been confirmed in the treatment of solid tumors, including non-small-cell lung cancer (NSCLC). However, the direct functional mechanisms of tumor lethality mediated by apatinib and the precise mechanisms of drug resistance are largely unknown. In this study, we demonstrated that apatinib could reprogram glutamine metabolism in human NSCLC via a mechanism involved in amino acid metabolic imbalances. Apatinib repressed the expression of GLS1, the initial and rate-limiting enzyme of glutamine catabolism. However, the broken metabolic balance led to the activation of the amino acid response (AAR) pathway, known as the GCN2/eIF2α/ATF4 pathway. Moreover, activation of ATF4 was responsible for the induction of SLC1A5 and ASNS, which promoted the consumption and metabolization of glutamine. Interestingly, the combination of apatinib and ATF4 silencing abolished glutamine metabolism in NSCLC cells. Moreover, knockdown of ATF4 enhanced the antitumor effect of apatinib both in vitro and in vivo. In summary, this study showed that apatinib could reprogram glutamine metabolism through the activation of the AAR pathway in human NSCLC cells and indicated that targeting ATF4 is a potential therapeutic strategy for relieving apatinib resistance.

DOI: https://doi.org/10.1038/s41419-022-05079-y
Pol J Pathol. 2022 ;pii: 47245. [Epub ahead of print]73(1): 1-5

Claudin 6 is associated with a short survival and a short recurrent free interval in non-small cell lung carcinoma.

Ylermi Soini, Risto Pirinen, Kumi Takasawa, Makoto Osanai, Akira Takasawa.

  We investigated the expression of claudin 6 in non-small-cell lung carcinomas (NSCLC) by immunohistochemistry. Samples of 164 patients with NSCLC were studied by immunohistochemistry. Claudin 6 was expressed in 42 % of cases. Its expression was significantly more frequent in adeno- than in squamous cell carcinoma (p = 0.002). There was no association between the TNM status and claudin 6 expression. Claudin 6 associated with a poor prognosis of the patients and with a short recurrence-free interval (p = 0.002, p < 0.001). The association with survival had independent prognostic value (p = 0.011). The results show that claudin 6 can be regarded as a marker of poor prognosis in lung cancer. This is different to some other cancers, such as breast and cervical carcinoma suggesting that claudin 6 probably induces other cellular pathways in neoplastic lung cells than in those tumors. In lung cancer, adenocarcinomas were most abundantly positive indicating a higher linkage of claudin 6 to glandular differentiation.

Keywords:   carcinoma; immunohistochemistry; lung; survival; claudin

DOI:  https://doi.org/10.5114/pjp.2022.117171
Mol Cancer. 2022 07 16. 21(1): 147

LINE-1 promotes tumorigenicity and exacerbates tumor progression via stimulating metabolism reprogramming in non-small cell lung cancer.

Zeguo Sun, Rui Zhang, Xiao Zhang, Yifei Sun, Pengpeng Liu, Nancy Francoeur, Lei Han, Wan Yee Lam, Zhengzi Yi, Robert Sebra, Martin Walsh, Jinpu Yu, Weijia Zhang.

   BACKGROUND: Long Interspersed Nuclear Element-1 (LINE-1, L1) is increasingly regarded as a genetic risk for lung cancer. Transcriptionally active LINE-1 forms a L1-gene chimeric transcript (LCTs), through somatic L1 retrotransposition (LRT) or L1 antisense promoter (L1-ASP) activation, to play an oncogenic role in cancer progression.
METHODS: Here, we developed Retrotransposon-gene fusion estimation program (ReFuse), to identify and quantify LCTs in RNA sequencing data from TCGA lung cancer cohort (n = 1146) and a single cell RNA sequencing dataset then further validated those LCTs in an independent cohort (n = 134). We next examined the functional roles of a cancer specific LCT (L1-FGGY) in cell proliferation and tumor progression in LUSC cell lines and mice.
RESULTS: The LCT events correspond with specific metabolic processes and mitochondrial functions and was associated with genomic instability, hypomethylation, tumor stage and tumor immune microenvironment (TIME). Functional analysis of a tumor specific and frequent LCT involving FGGY (L1-FGGY) reveal that the arachidonic acid (AA) metabolic pathway was activated by the loss of FGGY through the L1-FGGY chimeric transcript to promote tumor growth, which was effectively targeted by a combined use of an anti-HIV drug (NVR) and a metabolic inhibitor (ML355). Lastly, we identified a set of transcriptomic signatures to stratify the LUSC patients with a higher risk for poor outcomes who may benefit from treatments using NVR alone or combined with an anti-metabolism drug.
CONCLUSIONS: This study is the first to characterize the role of L1 in metabolic reprogramming of lung cancer and provide rationale for L1-specifc prognosis and potential for a therapeutic strategy for treating lung cancer.
TRIAL REGISTRATION: Study on the mechanisms of the mobile element L1-FGGY promoting the proliferation, invasion and immune escape of lung squamous cell carcinoma through the 12-LOX/Wnt pathway, Ek2020111. Registered 27 March 2020 - Retrospectively registered.

Keywords:  FGGY; LINE-1; LUAD; LUSC; Metabolic; NSCLC; Transposable element

DOI:  https://doi.org/10.1186/s12943-022-01618-5
Clin Transl Oncol. 2022 Jul 23.

Excess weight and anti-PD-1 immune checkpoint inhibitor's outcomes in non-small cell lung cancer.

Jacobo Rogado, Fernando Pozo, Kevin Troulé, José Miguel Sánchez-Torres, Nuria Romero-Laorden, Rebeca Mondejar, Olga Donnay, Anabel Ballesteros, Vilma Pacheco-Barcia, Javier Aspa, Fátima Al-Shahrour, Arantzazu Alfranca, Ramon Colomer.

   PURPOSE: Immune checkpoint inhibitors are one of the most effective treatments available in advanced non-small cell lung cancer. However, at present, there are no clinical or analytical biomarkers that define which patients benefit with certainty from these treatments. In our study, we evaluated whether excess weight could be a good predictive biomarker of benefit from these drugs.
METHODS: We studied a population of 79 patients, divided into a study group with 39 patients diagnosed with non-small cell lung cancer treated with immunotherapy and 40 patients in a control group, diagnosed with different advanced cancers, treated with non-immunotherapy treatment. We analyzed according to the presence of excess weight or not, the treatment's outcome in the study group and in the control group (objective response, and progression-free and overall survival).
RESULTS: In our study, we detected a better response rate to immunotherapy in patients with excess weight (62.50 vs 26.08%, OR 4.72, p = 0.02), and a better median progression-free survival (14.19 vs 5.03 months, HR 0.50, p = 0.058) and median overall survival (33.84 months vs 20.76 months, HR 0.43, p = 0.01) in the study group. These findings were specific to the immunotherapy group since in the control group, with patients who did not receive immune checkpoint inhibitors, these findings were not found.
CONCLUSION: Our study suggests that patients with excess weight who receive anti-PD-1 immune checkpoint inhibitors diagnosed with non-small cell lung cancer have a better outcome. This effect is specific to patients receiving immunotherapy.

Keywords:  Excess weight; Immune checkpoint inhibitors; Immunotherapy; Non-small cell lung cancer; Outcome predictors

DOI:  https://doi.org/10.1007/s12094-022-02887-8
Ann Oncol. 2022 Jul 15. pii: S0923-7534(22)01827-0. [Epub ahead of print]

Circulating L-Arginine predicts the survival of cancer patients treated with immune checkpoint inhibitors.

F Peyraud, J-P Guegan, D Bodet, I Nafia, L Fontan, C Auzanneau, S Cousin, G Roubaud, M Cabart, F Chomy, F Le Loarer, N Chaput, F-X Danlos, D Planchard, C Even, M Khettab, L Tselikas, B Besse, F Barlesi, J-C Soria, A Marabelle, A Bessede, A Italiano.

   BACKGROUND: The discovery of immune checkpoint inhibitors (ICIs) has revolutionized the systemic approach to cancer treatment. However, most patients receiving ICIs do not derive benefits. Therefore, it is crucial to identify reliable predictive biomarkers of response to ICIs. One important pathway in regulating immune cell reactivity is L-arginine (ARG) metabolism, essential to T-cell activation. We therefore aimed to evaluate the association between baseline plasma ARG levels and the clinical benefit of ICIs.
PATIENTS AND METHODS: The correlation between ARG levels and clinical ICI activity was assessed by analyzing plasma samples obtained before treatment onset in two independent cohorts of patients with advanced cancer included in two institutional molecular profiling programs (BIP, NCT02534649, n = 77; PREMIS, NCT03984318, n = 296) and from patients in a phase 1 first-in-human study of budigalimab monotherapy (NCT03000257). Additionally, the correlation between ARG levels and ICI efficacy in preclinical settings was evaluated using a syngeneic mouse model of colorectal cancer responsive to ICIs. Using matched PBMC plasma samples, we analyzed the correlation between ARG levels and PBMC features through multiplexed flow cytometry analysis.
RESULTS: In both discovery and validation cohorts, low ARG levels at baseline (<42 μM) were significantly and independently associated with a worse clinical benefit rate, progression-free survival, and overall survival. Moreover, at the preclinical level, the tumor rejection rate was significantly higher in mice with high baseline ARG levels than in those with low ARG levels (85.7% versus 23.8%; P = 0.004). Finally, PBMC immunophenotyping showed that low ARG levels were significantly associated with increased PD-L1 expression in several immune cell subsets from the myeloid lineage.
CONCLUSION: We demonstrate that baseline ARG levels predict ICI response. Plasma ARG quantification may therefore represent an attractive biomarker to tailor novel therapeutic regimens targeting the ARG pathway in combination with ICIs.

Keywords:  arginine metabolism; biomarker; cancer immunotherapy; immune checkpoint inhibitor

DOI:  https://doi.org/10.1016/j.annonc.2022.07.001