Targeting cancer metabolism in the era of precision oncology

Abstract

One hundred years have passed since Warburg discovered alterations in cancer metabolism, more than 70 years since Sidney Farber introduced anti-folates that transformed the treatment of childhood leukaemia, and 20 years since metabolism was linked to oncogenes. However, progress in targeting cancer metabolism therapeutically in the past decade has been limited. Only a few metabolism-based drugs for cancer have been successfully developed, some of which are in - or en route to - clinical trials. Strategies for targeting the intrinsic metabolism of cancer cells often did not account for the metabolism of non-cancer stromal and immune cells, which have pivotal roles in tumour progression and maintenance. By considering immune cell metabolism and the clinical manifestations of inborn errors of metabolism, it may be possible to isolate undesirable off-tumour, on-target effects of metabolic drugs during their development. Hence, the conceptual framework for drug design must consider the metabolic vulnerabilities of non-cancer cells in the tumour immune microenvironment, as well as those of cancer cells. In this Review, we cover the recent developments, notable milestones and setbacks in targeting cancer metabolism, and discuss the way forward for the field.

Fig. 1. Oncogenic factors regulate cancer cell metabolism.

The deregulated tyrosine kinase receptors activate RAS or PI3K, MYC and/or mTOR. mTORC1 increases protein synthesis from MYC-induced mRNAs to enhance influx of amino acids (AAs, including glutamine), glucose and fatty acids to drive fatty acid, nucleotide and protein synthesis. Hypoxia-inducible factors HIF1α and HIF2α are induced by mTORC1 or hypoxia, resulting in activation of the glycolytic pathway with the conversion of glucose to lactate, which is exported extracellularly. MYC transactivates genes involved in glycolysis and shunting of 3-phosphoglycerate to produce serine, which is converted to glycine and contributes to one-carbon (1C) metabolism. MYC also induces glutamine metabolism, enhancing glutamine and glucose uptake and their catabolism in the tricarboxylic acid (TCA) cycle, providing scaffolds for fatty acids and nucleotide synthesis. Oxygen is shown to assist the mitochondrial electron transport chain (ETC, with complexes I–V shown) or inhibit HIF1α and HIF2α by mediating its proteasomal degradation. aKG, α-ketoglutarate; ARNT, aryl hydrocarbon receptor nuclear translocator; MAX, MYC-associated factor X; OAA, oxaloacetate; Suc-CoA, succinyl-Coenzyme A.

Fig. 2. Inhibitors of glucose metabolism.

Glucose is taken up into the cell by glucose transporters (GLUT) and phosphorylated by hexokinases HK1 and HK2. Glucose 6-phosphate (P) and its downstream intermediates can either be converted to pyruvate or fuel biosynthesis through the hexosamine biosynthesis pathway, the pentose phosphate pathway (PPP), via glycerol 3-P production or via serine biosynthesis pathways. Hexosamine has a key role in glycosylation. The PPP provides ribose 5-P for nucleotide synthesis and NADPH. Glycerol 3-P provides the backbone for lipid synthesis. Serine biosynthesis has a key part in amino acid metabolism and nucleotide metabolism through control of one-carbon (1C) metabolism (see Fig. 5). Pyruvate can either enter the tricarboxylic acid (TCA) cycle as acetyl-CoA through the mitochondrial pyruvate carrier (MPC) and pyruvate dehydrogenase, be converted to lactate by lactate dehydrogenase (LDH) and exported through the monocarboxylate transporter (MCT) or be converted to alanine via glutamic–pyruvic transaminase (GPT). Inhibitors (blue) and activators (purple) of key enzymes (red) or transporters (white) are shown. In addition to producing energy by contributing reducing equivalents to the electron transport chain, the TCA cycle is an important source of aspartate for nucleotide metabolism (see Fig. 5). The conversion of pyruvate to lactate has a key role in maintaining cellular NAD⁺ to NADH ratios. aKG, α-ketoglutarate; OAA, oxaloacetate; PDH, pyruvate dehydrogenase; PHGDH, phosphoglycerate dehydrogenase; PKM2, pyruvate kinase muscle isozyme 2; SHMT, serine hydroxymethyl transferase.

Fig. 3. Inhibitors of glutamine metabolism.

Glutamine acts as a key carbon and nitrogen donor for biosynthesis. Glutamine is taken up by transporters, including alanine–serine–cysteine transporter 2 (ASCT2, also known as SLC1A5) and can be exported or imported through large neutral amino acid transporter 1 (LAT1, also known as SLC7A5) in exchange for branched-chain amino acids (BCAAs). Following its production from glutamine by glutaminase enzymes (GLS1 and GLS2), glutamate can be converted to α-ketoglutarate (aKG), be exported in exchange for cystine by the xCT transporter, or fuel proline biosynthesis. Glutamate can be converted to aKG by either glutamate dehydrogenase (GDH) or aminotransferases. The glutamic-oxaloacetic transaminase (GOT) produces aspartate, which has a key part in nucleotide synthesis. Glutamine can act as a nitrogen donor for the synthesis of asparagine, hexosamine, purine and pyrimidine. Aminotransferases use glutamate as a nitrogen donor for the synthesis of alanine, serine and aspartate. Glutamate, cystine-derived cysteine and serine-derived glycine contribute to glutathione biosynthesis, which has a key role in modulating oxidative stress. Inhibitors of key enzymes or transporters are shown (blue). ASNS, asparagine synthetase; CAD, carbamoyl-phosphate synthetase 2, aspartate transcarbamylase and dihydroorotase; CTPS, CTP synthase; GFAT, fructose 6-phosphate transaminase (GFPT1, GFPT2); GMPS, guanine monophosphate synthase; GPT, glutamic–pyruvic transaminase; OAA, oxaloacetate; PFAS, phosphoribosylformylglycinamidine synthase; PPAT, phosphoribosyl pyrophosphate amidotransferase; PSAT1, phosphoserine aminotransferase 1.

Fig. 4. Inhibitors of fatty acid synthesis.

Fatty acid synthesis can be used along with exogenous fatty acids for lipid production, which can be used to produce membranes and lipid droplets and to modulate signalling pathways. Mitochondrial acetyl-CoA derived from fatty acid oxidation (which can be an important tricarboxylic acid (TCA) cycle carbon source in some cancers), glucose or other sources can condense with oxaloacetate (OAA) to form citrate, which can then be exported from the mitochondrion. Citrate and acetate — via ATP citrate lyase (ACLY) and synthetase short-chain family member 2 (ACSS2), respectively — are two major sources of cytoplasmic acetyl-CoA, from which acetyl-CoA carboxylase (ACC1 and ACC2) makes malonyl-CoA, which is then cyclically extended by the addition of carbons from acetyl-CoA by fatty acid synthase (FASN) to make saturated fatty acids. Fatty acids are desaturated by stearoyl-CoA desaturase 1 (SCD1). Membrane desaturation has a key role in maintaining membrane fluidity. Fatty acid catabolism is initiated with the formation of fatty acyl-CoA by an acyl-CoA ligase. Fatty acyl-CoA is converted by carnitine palmitoyltransferase 1 (CPT1) to an acylcarnitine, which is then imported into the mitochondrion via carnitine–acylcarnitine translocase (CAT, SLC25A20). Inside the mitochondrion, CPT2 converts the acyl-carnitine back to a fatty acyl-CoA, which can then be cyclically oxidized to two carbon acetyl-CoA molecules. Inhibitors of key enzymes or transporters are shown (blue). aKG, α-ketoglutarate; CoA, Coenzyme A; CTP, citrate transporter protein (SLC25A1); PDH, pyruvate dehydrogenase.

Fig. 5. Inhibitors of nucleotide synthesis.

a | One-carbon (1C) metabolism. Nucleotide synthesis uses ribose 5-P produced by the pentose phosphate pathway (PPP) and aspartate produced from oxaloacetate, as well as glycine and tetrahydrofolate methyl donors — methylene-THF (5,10-CH-THF) and formyl-THF (10-CHO-THF) — arising from 1C metabolism linked to the conversion of serine to glycine. 1C metabolism occurs in both the cytoplasm and mitochondria. b | Purine synthesis is a multistep, multienzyme pathway that uses ribose 5-P, glutamine (Gln), glycine (Gly), aspartate (Asp) and 10-CHO-THF to make inosine monophosphate (IMP). IMP is converted to ADP and GDP, which can then be converted to dADP and dGDP. c | Pyrimidine synthesis is a multistep process that uses phosphoribosyl pyrophosphate (PRPP) as a scaffold to produce UDP from glutamine, carbonate and aspartate. Ribonucleotide reductase (RNR) converts UDP to dUDP and CDP to dCDP. Thymidylate synthase (TYMS), which can be inhibited by the clinical agents pemetrexed or 5-fluorouracil (5-FU), converts dUMP to dTMP. CoQH2, reduced Coenzyme Q; DHF, dihydrofolate; DHODH, dihydroorotate dehydrogenase; ETC, electron transport chain; GCS, glycine cleavage system; HCO₃, bicarbonate; IMPDH, inosine monophosphate dehydrogenase; MTHFD1, methylenetetrahydrofolate dehydrogenase 1; MTHFD1L, methylenetetrahydrofolate dehydrogenase 1-like; MTHFD2, methylenetetrahydrofolate dehydrogenase 2; MTX, methotrexate; PHGDH, phosphoglycerate dehydrogenase; PPAT, phosphoribosyl pyrophosphate amidotransferase; RNR, ribonucleotide reductase; SHMT1, serine hydroxymethyl transferase 1.

Fig. 6. Structures of enzymes or transporter bound to high-affinity small-molecule inhibitors.

a | Tetramer of glutaminase 1 (GLS1) bound to the CB-839 allosteric inhibitor (arrow) at the tetramerization interface. b | NCGC00420737-09 inhibitor (arrow) bound to tetramer of lactate dehydrogenase A (LDHA) with NAD (dashed arrow). c | GSK compound 27, a 2-amido-6-benzenesulfonamide glucosamine inhibitor (arrow), bound to hexokinase 2 (HK2) with different domains colour highlighted. d | AZ3965 inhibitor (arrow) bound to monocarboxylate transporter 1 (MCT1) (red transmembrane helices) and basigin (yellow sheet linked to a single transmembrane red helix on the right) as determined by cryogenic electron microscopy. The Protein Database IDs are: GLS1 (5HL1); LDHA (6Q13); HK2 (5HFU) and MCT1 (6LLY). Structures are displayed by iCn3D at the NCBI structure website (https://www.ncbi.nlm.nih.gov/Structure/icn3d/full.html).