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Ref Type Journal Article
PMID (27641501)
Authors Sykes DB, Kfoury YS, Mercier FE, Wawer MJ, Law JM, Haynes MK, Lewis TA, Schajnovitz A, Jain E, Lee D, Meyer H, Pierce KA, Tolliday NJ, Waller A, Ferrara SJ, Eheim AL, Stoeckigt D, Maxcy KL, Cobert JM, Bachand J, Szekely BA, Mukherjee S, Sklar LA, Kotz JD, Clish CB, Sadreyev RI, Clemons PA, Janzer A, Schreiber SL, Scadden DT
Title Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia.
Journal Vol Issue Date Pages Journal Short Title
Cell 167 1 2016 Sep 22 171-186.e15 Cell
URL
Abstract Text While acute myeloid leukemia (AML) comprises many disparate genetic subtypes, one shared hallmark is the arrest of leukemic myeloblasts at an immature and self-renewing stage of development. Therapies that overcome differentiation arrest represent a powerful treatment strategy. We leveraged the observation that the majority of AML, despite their genetically heterogeneity, share in the expression of HoxA9, a gene normally downregulated during myeloid differentiation. Using a conditional HoxA9 model system, we performed a high-throughput phenotypic screen and defined compounds that overcame differentiation blockade. Target identification led to the unanticipated discovery that inhibition of the enzyme dihydroorotate dehydrogenase (DHODH) enables myeloid differentiation in human and mouse AML models. In vivo, DHODH inhibitors reduced leukemic cell burden, decreased levels of leukemia-initiating cells, and improved survival. These data demonstrate the role of DHODH as a metabolic regulator of differentiation and point to its inhibition as a strategy for overcoming differentiation blockade in AML.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Brequinar Brequinar 0 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
Brequinar DUP 785|DUP785|DUP-785|NSC368390|NSC-368390|NSC 368390|Bipenquinate Brequinar (DUP 785) is a small molecule that selectively inhibits the activity of Dihydroorotate dehydrogenase (DHODH), potentially resulting in increased myeloid differentiation and decreased tumor burden (PMID: 27641501, PMID: 32525770).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References