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Targeting dihydroorotate dehydrogenase in acute myeloid leukemia
Zhihong Zeng1 and Marina Konopleva1,2
1Department of Leukemia and 2Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
E-mail: mkonople@mdanderson.org doi:10.3324/haematol.2018.197806
With their discovery of a promising inhibitor of dihy- droorotate dehydrogenase (DHODH), Wu and Wong et al. have made progress toward effective differentiation therapy for acute myeloid leukemia (AML).1 Their paper entitled “Pharmacological inhibition of dihy- droorotate dehydrogenase induces apoptosis and differenti- ation of acute myeloid leukemia cells,” published in this issue of Haematologica, reports that this inhibitor had signifi- cant anti-leukemia efficacy in vitro and in vivo.1
DHODH is an enzyme that catalyzes the oxidation of dihydroorotate into orotate in intracellular de novo pyrimi- dine synthesis. Pyrimidine bases are essential for cellular metabolism and cell growth, and are considered important precursors in nucleotide, glycoprotein, and phospholipid biosynthesis and nucleotide recycling.2 Dysregulation of and functional dependency on pyrimidine biosynthesis have been found in diverse solid tumors.3 As a key enzyme regu- lating this process, DHODH has been identified as a syn- thetically lethal target in tumors that carry specific genetic mutations, including PTEN-deficient and triple-negative breast cancer,4,5 BRAFV600E–mutant melanoma,6 RAS/LKB1 double-mutant lung cancer,7 and KRAS-mutated pancreatic cancer.8
AML is a highly heterogeneous hematologic malignancy, characterized by uncontrolled growth of immature hematopoietic stem/progenitor cells and impaired differenti- ation.9,10 The long-term survival rate of AML patients who receive standard therapies remains poor.11 Differentiation therapy was proposed decades ago with the goal of promot- ing the normal process of hematopoietic maturation from self-renewing progenitors to terminally differentiated effec- tor cells,12 but its success has been limited except in specific genetic subtypes of AML. For example, all-trans retinoic acid induces differentiation and remissions in patients with acute promyelocytic leukemia.13 Inhibitors of isocitrate dehydro- genase (IDH) have been approved more recently for treat- ment of AML carrying IDH1/2 mutations, and the activity of these inhibitors is associated with clinical and morphological signs of myeloid differentiation.14
Recent pre-clinical findings by Sykes et al. showed that DHODH is a metabolic regulator in the pyrimidine synthesis pathway and a new metabolic target in differentiation ther- apy for AML.15 Inhibition of DHODH effectively enabled cell differentiation and had anti-leukemia efficacy in vitro and in vivo.15 This discovery opens up a new perspective in differ- entiation therapy for AML carrying complex and heteroge- neous combinations of gene mutations. It leads to pharma- cological intervention via development of novel, potent, and optimized DHODH inhibitors for clinical applications and to studies aiming to determine the mechanisms underlying DHODH inhibition–mediated AML differentiation.
In this issue of Haematologica, Wu and Wang et al. confirm the essential role of DHODH in AML survival and differen-
tiation.1 Using CRISPR-Cas9–mediated gene knockout, the authors observed induction of apoptosis and cellular differ- entiation in DHODH-knockout AML cells. Through analysis of RNA sequencing data for 173 primary AML samples, they found that DHODH and MYC, a key regulator of myeloid cell proliferation and differentiation, are coordinately expressed in AML. Using structure-based virtual screening of 337 natural products, the research team identified isobavachalcone, a chalcone derived from the traditional Chinese medicine Psoralea corylifolia, as a potent and selective inhibitor of DHODH. Isobavachalcone, a competitive inhibitor of CoQ0 and a noncompetitive inhibitor of the DHODH substrate dihydroorotate, binds the docking site of the “ubiquinone channel” of the DHODH complex, interact- ing structurally with and stabilizing DHODH. Treatment with isobavachalcone led to dose-dependent induction of apoptosis and myeloid differentiation in the cell lines tested. The on-target effect mediated by isobavachalcone’s inhibi- tion of DHODH is supported by the findings that uridine, a downstream metabolite of DHODH in the pyrimidine syn- thesis pathway, was depleted in isobavachalcone-treated cells and that growth inhibition was rescued by uridine sup- plementation.1 Mechanistically, the apoptosis and cell differ- entiation induced by isobavachalcone’s inhibition of DHODH was found to occur, at least in part, through c- MYC suppression, by directly reducing its gene transcription and degrading c-MYC protein via proteasome dependent degradation and downregulation of the enzyme O-linked N- acetylglucosamine transferase that normally stabilizes MYC via transfer of GlcNAc from uridine diphosphate-GlcNAc to MYC.16,17 Notably, O-GlcNAc post-translational modification similarly stabilizes additional proteins such as AKT and the TET family of proteins.18 In a subcutaneous AML cell line xenograft model, isobavachalcone treatment suppressed tumor growth, and this effect was accompanied by inhibi- tion of DHODH activity and induction of apoptosis of tumor cells.1 Oral administration of isobavachalcone was well tolerated in mice. A combination of isobavachalcone and adriamycin (doxorubicin), an agent widely used in AML therapy, synergistically induced cell death and restored sen- sitivity of doxorubicin-resistant AML cells in vitro; this com- bination also led to cell differentiation and prolonged mouse survival in vivo in a systemic AML cell line xenograft leukemia model, analogous to the report of the efficacy of doxorubicin combined with the approved DHODH inhibitor leflunomide in triple-negative breast cancer.5 These data support the idea that isobavachalcone, an orally active DHODH inhibitor, might have clinical benefit in AML differ- entiation therapy.
The work by Wu and Wang et al. advances our knowledge of DHODH regulation in AML and offers a novel inhibitor with promise for differentiation therapy. The detailed mech- anisms underlying this activity, such as how the functional
haematologica | 2018; 103(9)
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