Impact of cancer metabolism on therapy resistance – Clinical implications. (December 2021)

• Record Type: Journal Article
• Authors: Gonçalves, Ana Cristina; Richiardone, Elena; Jorge, Joana; Polónia, Bárbara; Xavier, Cristina P.R.; Salaroglio, Iris Chiara; Riganti, Chiara; Vasconcelos, M. Helena; Corbet, Cyril; Sarmento-Ribeiro, Ana Bela
• Is Part Of: Drug resistance updates. Volume 59(2021)
• Publication Date: 2021-12
• Subjects: 18F-DOPA 18F-34-dihydroxyphenylalanine -- 18F-FDG 2-deoxy-2-[fluorine-18] fluoro-d-glucose -- 2-DG 2-deoxy-d-glucose -- 2HG 2-hydroxyglutarate -- 5-FU 5-fluorouracil -- AAD antiangiogenic drugs -- ABC ATP-binding cassette transporter -- ADT androgen deprivation therapy -- AI artificial intelligence -- ARE antioxidant response elements -- ASC adipose-derived mesenchymal stem cell -- Asn asparagine -- ASNS asparagine synthetase, ASS1, argininosuccinate synthase 1 -- BCAT1 branched-chain amino acid transaminase 1 -- BDNF brain-derived neurotrophic factor -- BPTES bis-2-(5-phenylacetamido-1, 3, 4-thiadiazol-2-yl)ethyl sulfide -- BSO buthionine sulfoximine -- BTKi Bruton's tyrosine kinase inhibitor -- C1P Cer-1-phosphate -- CAA cancer-associated adipocytes -- CAF cancer-associated fibroblasts -- CAXII carbonic anhydrase XII -- Cer ceramide -- CEBP-β CAAT enhancer binding protein-β -- CLCF1 cardiotrophin-like cytokine factor 1 -- cPLA2 cytosolic phospholipase A2 -- CSC cancer stem cells -- CSK C-terminal SRC kinase -- DON 6-diazo-5-oxo-l-norleucine -- DRM detergent-resistant membrane -- ECM extracellular matrix -- EGF epidermal growth factor -- EMA European Medicines Agency -- EMT epithelial-to- mesenchymal transition -- ENO enolase -- ER estrogen receptor -- ET endocrine therapy -- EVs extracellular vesicles -- FA fatty acid -- FAO Fatty acid oxidation -- FASN fatty acid synthase -- FDA Food and Drug Administration -- FGF fibroblast growth factor -- FPP farnesyl pyrophosphate -- G6PD glucose-6-phosphate dehydrogenase -- GCLC glutamate-cysteine ligase catalytic subunit -- GCN2 general control non-depressible 2 -- GGPP geranylgeranyl pyrophosphate -- GLS glutaminase -- GLUTs glucose transporters GPAT1, glycerol 3-phosphate acyltransferase -- GPER G-protein-coupled estrogen receptor -- GSH reduced glutathione -- GSSG oxidized glutathione -- H2O2 hydrogen peroxide -- HIF-1α hypoxia-inducible factor 1α -- HIF hypoxia-inducible factor -- HKII hexokinase II -- HMGCR 3-β-hydroxy-3-β-methyl glutaryl coenzyme A reductase -- HMGCS1 3-β-hydroxy-3-β-methylglutaryl coenzyme A synthase 1 -- ICIs immune checkpoint inhibitors -- IDH isocitrate dehydrogenase -- IDO1 indoleamine 2, 3-dioxygenase -- IFN-γ interferon gamma -- LD lipid droplets -- LDH lactate dehydrogenase -- LDL low density lipoprotein -- LKB1 liver kinase B1 -- LPA lysophosphatidate -- LPAR LPA receptor -- LPCAT2 lysoPC acyltransferase 2 -- LXR liver X receptor -- LysoPL lysophospholipids -- MCT monocarboxylate transporter -- MDR multidrug resistance -- ME malic enzyme -- MPC mitochondrial pyruvate carrier -- MSI mass spectrometry imaging -- mtDNA mitochondrial DNA -- NADPH reduced nicotinamide adenine dinucleotide phosphate -- NHE Na+/H+exchanger -- NMR nuclear Magnetic Resonance -- NQO1 NAD(P)H quinone oxidoreductase -- O2− superoxide anion -- OH hydroxyl radical -- OXPHOS oxidative phosphorylation -- P-gp P-glycoprotein -- PAG1 phosphoprotein associated with glycosphingolipid-enriched microdomains -- PDH pyruvate dehydrogenase -- PDK pyruvate dehydrogenase kinase -- PET-CT positron emission tomography coupled to computed tomography -- PFK phosphofructokinase -- PGC-1α peroxisome proliferator-activated receptor gamma coactivator 1-alpha -- PGD phosphogluconate dehydrogenase -- pHe extracellular pH -- PHGDH phosphoglycerate dehydrogenase -- PKM2 pyruvate kinase M2 -- PL phospholipid -- PLIN4 perilipin 4 -- PPAR peroxisome proliferator activated receptor -- PPI proton pump inhibitors -- PPP pentose phosphate pathway -- PTMA prothymosin α -- ROS reactive oxygen species -- RTK tyrosine kinase receptors -- S1P Sph-1-phosphate -- SAT1 spermidine/spermine N1-acetyltransferase -- SCD-1 stearoyl-coenzyme A desaturase-1 -- SLC solute carrier transporters -- SMs sphingomyelins -- SOD superoxide dismutase -- Sph sphingosine -- SREBP1 sterol regulatory element-binding protein 1 -- STAT3 signal transducer and activator of transcription 3 -- TCA tricarboxylic acid -- TDO tryptophan 2, 3-dioxygenase -- TG triglyceride -- TIF tumor interstitial fluid -- TKI tyrosine kinase inhibitors -- TME tumor microenvironment -- TPP+ phenol triphenyl alkyl phosphonium -- TSG tumor suppressor gene -- V-H+-ATPase vacuolar H+-ATPase -- VEGF vascular endothelial growth factor -- YAP yes-associated protein -- α-KG α-ketoglutarate; Cancer metabolism -- Therapy resistance -- Tumor microenvironment -- Intratumor heterogeneity -- Metabolic plasticity -- Glycolysis -- Oxidative phosphorylation; Drug resistance in cancer cells -- Periodicals; Cancer -- Chemotherapy -- Periodicals; 616.994061
• DOI: 10.1016/j.drup.2021.100797
• Languages: English
• ISSNs: 1368-7646

Abstract

Abstract: Despite an increasing arsenal of anticancer therapies, many patients continue to have poor outcomes due to the therapeutic failures and tumor relapses. Indeed, the clinical efficacy of anticancer therapies is markedly limited by intrinsic and/or acquired resistance mechanisms that can occur in any tumor type and with any treatment. Thus, there is an urgent clinical need to implement fundamental changes in the tumor treatment paradigm by the development of new experimental strategies that can help to predict the occurrence of clinical drug resistance and to identify alternative therapeutic options. Apart from mutation-driven resistance mechanisms, tumor microenvironment (TME) conditions generate an intratumoral phenotypic heterogeneity that supports disease progression and dismal outcomes. Tumor cell metabolism is a prototypical example of dynamic, heterogeneous, and adaptive phenotypic trait, resulting from the combination of intrinsic [(epi)genetic changes, tissue of origin and differentiation dependency] and extrinsic (oxygen and nutrient availability, metabolic interactions within the TME) factors, enabling cancer cells to survive, metastasize and develop resistance to anticancer therapies. In this review, we summarize the current knowledge regarding metabolism-based mechanisms conferring adaptive resistance to chemo-, radio-and immunotherapies as well as targeted therapies. Furthermore, we report the role of TME-mediated intratumoral metabolic heterogeneity in therapy resistance and how adaptations in amino acid, glucose, and lipid metabolism support the growth of therapy-resistant cancers and/or cellular subpopulations. We also report the intricate interplay between tumor signaling and metabolic pathways in cancer cells and discuss how manipulating key metabolic enzymes and/or providing dietary changes may help to eradicate relapse-sustaining cancer cells. Finally, in the current era of personalized medicine, we describe the strategies that may be applied to implement metabolic profiling for tumor imaging, biomarker identification, selection of tailored treatments and monitoring therapy response during the clinical management of cancer patients.