The strategic roles of four enzymes in the interconnection between metabolism and oncogene activation in non-small cell lung cancer: Therapeutic implications. (July 2022)

• Record Type: Journal Article
• Authors: Icard, Philippe; Simula, Luca; Fournel, Ludovic; Leroy, Karen; Lupo, Audrey; Damotte, Diane; Charpentier, Marie Christine; Durdux, Catherine; Loi, Mauro; Schussler, Olivier; Chassagnon, Guillaume; Coquerel, Antoine; Lincet, Hubert; De Pauw, Vincent; Alifano, Marco
• Is Part Of: Drug resistance updates. Volume 63(2022)
• Publication Date: 2022-07
• Subjects: AA Amino acid -- ACC Acetyl-CoA carboxylase -- ACLY ATP Citrate Lyase -- ACSL Acyl-coenzyme A synthetase long-chain isoform -- ACSS2 Acetyl-CoA synthetase 2 -- ADP Adenosine diphosphate -- ASCT2/ SLC1A5 Alanine serine cysteine preferring transporter 2 -- ATP Adenosine triphosphate -- aKG α-ketoglutarate -- AKT Protein Kinase B -- ALK Anaplastic lymphoma kinase -- BRAF V-raf murine sarcoma viral oncogene homolog B1 -- CDK Cyclin-dependent kinase -- COX Cyclooxygenase -- CPS1 Carbamoyl phosphate synthetase-1 -- CSCs Cancer stem cells -- CT Chemotherapy -- Cyc Cyclin -- DCA Dichloroacetate -- DHAP Dihydroxyacetone phosphate -- DHODH Dihydroorotate dehydrogenase -- E2F1 E2F Transcription Factor 1 -- EGF Epidermal Growth Factor -- EGFR Epidermal Growth Factor Receptor -- EMT Epithelial to mesenchymal transition -- ERBB2 Erythroblastic oncogene B -- ERK Ras-dependent extracellular signal-regulated kinase -- EZH2 Enhancer of zeste homologue 2 -- F-1, 6-BP Fructose-1, 6-bisphosphate -- F-2, 6-BP Fructose-2, 6-bisphosphate -- FA Fatty acid -- FAS Fatty acid synthesis -- FASN Fatty acid synthase -- FBPase1 Fructose-1, 6-bisphosphatase 1 -- 18F-FDG 18F-fluoro-Deoxy-glucose -- FGF-β Fibroblast growth factor-β -- FGFR1 Fibroblast growth factor receptor type 1 -- FOXO Forkhead box O -- G3P Glyceraldehyde 3-phosphate -- GAPDH Glyceraldehyde-3-phosphate dehydrogenase -- GCN5 General control non-depressible 5 -- GDP Guanosine biphosphate -- GLS1 Glutaminase 1 -- GLUD Glutamate dehydrogenase -- GLUT Glucose transporter -- GOT1 Glutamic-oxaloacetic transaminase 1 -- GS Glutamine synthetase -- GTP Guanosine triphosphate -- HBP Hexosamine biosynthesis pathway -- HER2 Human epidermal growth factor receptor 2 -- 2-HG 2-hydroxyglutarate -- HGF Hepatocyte growth factor -- HIF-1α Hypoxia‑induced factor‑1α -- HK2 Hexokinase 2 -- HMG-CoA 3-hydroxy-3-methyl-glutaryl-CoA -- IDH Isocitrate dehydrogenase -- IGFR Insulin-like growth factor receptor -- IL-6 Interleukin-6 -- IL-6R Interleukin-6 receptor -- IT Immunotherapy -- JAK Janus tyrosine kinase -- KRAS Kristen rat sarcoma viral oncogene homolog -- LDHA Lactate dehydrogenase A -- LKB Liver Kinase B -- LOX Lipoxygenase -- LSCC Lung squamous-cell carcinoma -- LUAD Lung adenocarcinoma -- MAPK Mitogen-activated protein kinase -- MCT4 Monocarboxylate transporter 4 -- MDH Malate dehydrogenase -- ME Malic enzyme -- mTOR Mammalian target of rapamycin -- MUFA Monounsaturated fatty acid -- MVP Mevalonate pathway -- NAD+ Nicotinamide adenine dinucleotide -- NADPH H+, Nicotinamide adenine dinucleotide phosphate -- NSCLC Non-small cell lung carcinoma -- OAA Oxaloacetate -- OXPHOS Oxidative phosphorylation -- PARP Poly (ADP-ribose) polymerase -- PD-1 Programmed cell Death death-1 -- PDH Pyruvate dehydrogenase -- PDK1 Pyruvate dehydrogenase kinase 1 -- PD-L1 Programmed death ligand 1 -- PEP Phosphoenolpyruvate -- PET/CT Positron emission computed tomography -- PFK1/ PFKP Phosphofructokinase 1 -- PFK2/ PFKFB3 Phosphofructokinase 2 -- PGK1 Phosphoglycerate kinase 1 -- PHD Prolyl 4-hydroxylase -- PI3K Phosphatidylinositol-3-kinase -- PI3P Phosphatidylinositol 3-phosphate -- PK Pyruvate kinase -- PKM2 Pyruvate kinase muscle embryonic isozyme 2 -- PPAT Phosphoribosyl pyrophosphate amidotransferase -- PPP Pentose phosphate pathway -- PTEN Phosphatase and tensin homolog deleted on chromosome 10 -- PUFA Polyunsaturated fatty acid -- R5P Ribose 5-phosphate -- RALGDS Ral guanine nucleotide dissociation stimulator -- RIP Receptor Interacting Protein kinase -- RT Radiotherapy -- S1P Sphingosine-1-phosphate -- SCLC Small cell lung cancer -- SDH Succinate dehydrogenase -- SIRT Sirtuin -- SOS1 Son of sevenless homolog 1 -- SphK2 Sphingosine kinase 2 -- SREBP1 Sterol regulatory element-binding protein -- STAT Signal transducers and activators of transcription -- TCA Tricarboxylic acid -- TGF Transforming growth factor -- TGFBR2 Transforming growth factor-β receptor 2 -- TKIs Tyrosine kinase inhibitors -- TKTL1 Transketolase-like 1 -- TME Tumor microenvironment -- TP53 Transformation-related protein 53 -- UCP1 Uncoupling protein 1 -- UCP3 Uncoupling protein 3 -- VEGF Vascular endothelial growth factor -- WT Wild type -- X5P Xylulose-5-phosphate -- YAP/TAZ Yes-associated protein/transcription co-activator; NSCLC -- PFK1 -- PI3K -- EGFR -- KRAS -- ACLY -- GLS1 -- PKM2; Drug resistance in cancer cells -- Periodicals; Cancer -- Chemotherapy -- Periodicals; 616.994061
• DOI: 10.1016/j.drup.2022.100852
• Languages: English
• ISSNs: 1368-7646

Abstract

Abstract: 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.