Expanding antitumor therapeutic windows by targeting cancer-specific nicotinamide adenine dinucleotide phosphate-biogenesis pathways

Figures & data

Figure 1 NADPH production from the oxidative PPP and one-carbon serine catabolism pathway.

Notes: Oxidative PPP uses glucose to generate NADPH via G6PD and 6PGD. G6PD is inhibited by then FDA-approved drug, 6-AN. NADP⁺ is generated through the NAD⁺ salvage pathway, where nicotinamide is converted to NMN via NAMPT. NADP⁺ is then formed by NADK. FK866 and GMX1778 inhibit NAMPT to block the production of NADP⁺, and therefore NADPH. During ROS stress, p53 positively regulates TIGAR to shunt glycolytic flux into the oxidative PPP. PKM2, which is overexpressed in many cancers, is inhibited by ROS, allowing glycolytic flux to be shuttled into the oxidative PPP for NADPH generation. The small-molecule compounds, ML-202/203/265, can positively modulate PKM2, thereby decreasing glycolytic flux into the oxidative PPP and blunting NADPH biogenesis during ROS.
Abbreviations: PPP, pentose phosphate pathway; NADPH, nicotinamide adenine dinucleotide phosphate; G6PD, glucose-6-phosphate dehydrogenase; 6PGD, 6-phosphogluconate dehydrogenase; 6-AN, 6-aminonicotinamide; NMN, nicotinamide mononucleotide; NAMPT, nicotinamide phosphoribosyltransferase; NADK, NAD⁺-kinase; ROS, reactive oxygen species; TIGAR, TP53-induced glycolysis and apoptosis regulator; PKM2, pyruvate kinase 2; G6P, glucose-6-phosphate; 6PG, 6-phosphogluconate; R5P, ribulose-5-phosphate; F16BP, fructose-1,6-bisphosphate; PEP, phosphoenolpyruvate; FDA, food and drug administration; NAD, nicotine adenine dinucleotide.

Figure 2 Agents targeting specific NADPH-biogenesis pathways.

Abbreviations: NADPH, nicotinamide adenine dinucleotide phosphate; BPTES, bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide 3; PPP, pentose phosphate pathway; PKM2, pyruvate kinase 2; ME, malic enzyme; GLS1, glutaminase 1; NAMPT, nicotinamide phosphoribosyltransferase; TS, thymidylate synthase; DHFR, dihydrofolate reductase; TIGAR, TP53-induced glycolysis and apoptosis regulator; PDAC, pancreatic ductal adenocarcinomas; SHMT2, serine hydroxymethyltransferase 2; MTHFD2, methylenetetrahydrofolate dehydrogenase 2.

Figure 3 One-carbon serine catabolism pathway.

Notes: Mitochondrial one-carbon serine metabolism pathway highlighting the production of NADPH from serine and folic acid through mitochondrial MTHFD2. THF is produced from DHF via folic acid by DHFR, which is inhibited by PEM or MTX. Additionally, DHF can be generated from dUMP via TS, which is also inhibited by PEM.
Abbreviations: NADPH, nicotinamide adenine dinucleotide phosphate; MTHFD2, methylenetetrahydrofolate dehydrogenase; THF, tetrahydrofolate; DHF, dihydrofolate; DHFR, dihydrofolate reductase; PEM, pemetrexed; MTX, methotrexate; dUMP, deoxyuridine monophosphate; TS, thymidylate synthase; SHMT2, serine hydroxymethyltransferase 2.

Figure 4 KRAS-reprogrammed glutamine metabolism in pancreatic cancer.

Notes: In KRAS-mutant pancreatic cancer, mitochondrial glutamine flux is reprogrammed to predominantly flux through GOT2, instead of the canonical GLUD1 pathway. The Asp produced from this reaction is shuttled to the cytoplasm to produce pyruvate and NADPH from malate via cytosolic ME1. TCA cycle-derived malate can also produce NADPH from mitochondrial ME2. Wild-type p53 inhibits both ME1 and ME2. BPTES and CB-839 are non-competitive small-molecule inhibitors of mitochondrial GLS1.
Abbreviations: GOT2, mitochondrial aspartate transaminase; GLUD1, glutamate dehydrogenase 1; Asp, aspartate; NADPH, nicotinamide adenine dinucleotide phosphate; ME1, malic enzyme 1; ME2, malic enzyme 2; BPTES, bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide 3; GLS1, glutaminase 1; MDH1, malate dehydrogenase 1; GOT1, cytosolic aspartate transaminase; OAA, oxaloacetate; αKG, α-ketoglutarate; TCA, tricarboxylic acid cycle.

Figure 5 NADPH biogenesis via IDH1.

Note: Cytoplasmic NADPH generated by IDH1 and mitochondrial NADPH generated by IDH2.
Abbreviations: IDH1, isocitrate dehydrogenase 1; NADPH, nicotinamide adenine dinucleotide phosphate; IDH2, isocitrate dehydrogenase 2; αKG, α-ketoglutarate.

Figure 6 Work flow to identify NSCLC-specific NADPH-biogenesis genes in a cancer-specific NADPH-biogenesis screen.

Abbreviations: NSCLC, non-small cell lung cancer; NADPH, nicotinamide adenine dinucleotide phosphate.

Figure 7 A cancer-specific NADPH-biogenesis screen.

Notes: Overexpression status of NADPH-biogenesis genes of interest assessed using Oncomine in NSCLC patients. Datasets used are described.^82–84
Abbreviations: NADPH, nicotinamide adenine dinucleotide phosphate; NSCLC, non-small cell lung cancer; G6PD, glucose-6-phosphate dehydrogenase; PKM2, pyruvate kinase 2; TIGAR, TP53-induced glycolysis and apoptosis regulator; SHMT2, serine hydroxymethyltransferase 2; MTHFD2, methylenetetrahydrofolate dehydrogenase; ME1, malic enzyme 1; ME2, malic enzyme 2; IDH1, isocitrate dehydrogenase 1; IDH2, isocitrate dehydrogenase 2; NAMPT, nicotinamide phosphoribosyltransferase.

Figure 8 Cancer-specific NADPH-biogenesis screen continued.

Notes: (A) Prognosis after radiation therapy in NSCLC patients. Dataset used is described;⁶⁷ (B) Correlation of genes of interest with upstream NADPH-biogenesis pathway members; (C) Mutant KRAS-dependence of MTHFD2 in a mouse model of NSCLC.
Abbreviations: NADPH, nicotinamide adenine dinucleotide phosphate; NSCLC, non-small cell lung cancer; MTHFD2, methylenetetrahydrofolate dehydrogenase; PKM2, pyruvate kinase 2; SHMT2, serine hydroxymethyltransferase 2; IDH2, isocitrate dehydrogenase 2; G6PD, glucose-6-phosphate dehydrogenase; TS, thymidylate synthase.

Figure 9 Screen results for MTHFD2 in NSCLC patients.

Notes: (A and B) mRNA expression of MTHFD2 in normal lung tissue vs NSCLC tissue in two different datasets from Oncomine; (C) Overall survival after radiation therapy in NSCLC patients segregated in high and low MTHFD2 expressers. Dataset used is described;⁶⁷ (D) Correlation of MTHFD2 with upstream NADPH-biogenesis pathway members; (E) Mutant KRAS-dependence of MTHFD2 in a mouse model of NSCLC (GSE40606).
Abbreviations: MTHFD2, methylenetetrahydrofolate dehydrogenase; NSCLC, non-small cell lung cancer; NADPH, nicotinamide adenine dinucleotide phosphate; SHMT2, serine hydroxymethyltransferase 2; TS, thymidylate synthase; HR, hazard ratio.

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