title: Co-targeting of convergent nucleotide biosynthetic pathways for leukemia eradication.
abstract: Pharmacological targeting of metabolic processes in cancer must overcome redundancy in biosynthetic pathways. Deoxycytidine (dC) triphosphate (dCTP) can be produced both by the de novo pathway (DNP) and by the nucleoside salvage pathway (NSP). However, the role of the NSP in dCTP production and DNA synthesis in cancer cells is currently not well understood. We show that acute lymphoblastic leukemia (ALL) cells avoid lethal replication stress after thymidine (dT)-induced inhibition of DNP dCTP synthesis by switching to NSP-mediated dCTP production. The metabolic switch in dCTP production triggered by DNP inhibition is accompanied by NSP up-regulation and can be prevented using DI-39, a new high-affinity small-molecule inhibitor of the NSP rate-limiting enzyme dC kinase (dCK). Positron emission tomography (PET) imaging was useful for following both the duration and degree of dCK inhibition by DI-39 treatment in vivo, thus providing a companion pharmacodynamic biomarker. Pharmacological co-targeting of the DNP with dT and the NSP with DI-39 was efficacious against ALL models in mice, without detectable host toxicity. These findings advance our understanding of nucleotide metabolism in leukemic cells, and identify dCTP biosynthesis as a potential new therapeutic target for metabolic interventions in ALL and possibly other hematological malignancies.
authors.affiliation: Department of Molecular and Medical Pharmacology; 2 Ahmanson Translational Imaging Division; 3 Department of Biomathematics; 4 The Pasarow Mass Spectrometry Laboratory, Department of Psychiatry and Biobehavioral Sciences and the Semel Institute for Neuroscience and Human Behavior; 5 Department of Biological Chemistry; and 6 Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095.
authors.forename: David A
authors.initials: DA
authors.lastname: Nathanson
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Armijo
authors.forename: Michelle
authors.initials: M
authors.lastname: Tom
authors.forename: Zheng
authors.initials: Z
authors.lastname: Li
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Dimitrova
authors.forename: Wayne R
authors.initials: WR
authors.lastname: Austin
authors.forename: Julian
authors.initials: J
authors.lastname: Nomme
authors.forename: Dean O
authors.initials: DO
authors.lastname: Campbell
authors.forename: Lisa
authors.initials: L
authors.lastname: Ta
authors.forename: Thuc M
authors.initials: TM
authors.lastname: Le
authors.forename: Jason T
authors.initials: JT
authors.lastname: Lee
authors.forename: Ryan
authors.initials: R
authors.lastname: Darvish
authors.forename: Ari
authors.initials: A
authors.lastname: Gordin
authors.forename: Liu
authors.initials: L
authors.lastname: Wei
authors.forename: Hsiang-I
authors.initials: HI
authors.lastname: Liao
authors.forename: Moses
authors.initials: M
authors.lastname: Wilks
authors.forename: Colette
authors.initials: C
authors.lastname: Martin
authors.forename: Saman
authors.initials: S
authors.lastname: Sadeghi
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Murphy
authors.forename: Nidal
authors.initials: N
authors.lastname: Boulos
authors.forename: Michael E
authors.initials: ME
authors.lastname: Phelps
authors.forename: Kym F
authors.initials: KF
authors.lastname: Faull
authors.forename: Harvey R
authors.initials: HR
authors.lastname: Herschman
authors.forename: Michael E
authors.initials: ME
authors.lastname: Jung
authors.forename: Johannes
authors.initials: J
authors.lastname: Czernin
authors.forename: Arnon
authors.initials: A
authors.lastname: Lavie
authors.forename: Caius G
authors.initials: CG
authors.lastname: Radu
mesh_terms: D000818:Animals; D053898:Biosynthetic Pathways / Q000187:drug effects / Q000502:physiology*; D003842:Deoxycytidine Kinase / Q000037:antagonists & inhibitors*; D003845:Deoxycytosine Nucleotides / Q000096:biosynthesis* / Q000378:metabolism; D060740:Disease Eradication / Q000379:methods*; D051379:Mice; D049268:Positron-Emission Tomography; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism*; D013936:Thymidine / Q000494:pharmacology
chemical_list: D003845:Deoxycytosine Nucleotides; C024107:2'-deoxycytidine 5'-triphosphate; D003842:Deoxycytidine Kinase; D013936:Thymidine