2. Academic Validation
  3. Targeting OXPHOS de novo purine synthesis as the nexus of FLT3 inhibitor-mediated synergistic antileukemic actions

Targeting OXPHOS de novo purine synthesis as the nexus of FLT3 inhibitor-mediated synergistic antileukemic actions

  • Sci Adv. 2022 Sep 16;8(37):eabp9005. doi: 10.1126/sciadv.abp9005.
Pu Zhang 1 2,  Lindsey T Brinton 1,  Mehdi Gharghabi 1 3,  Steven Sher 1,  Katie Williams 1,  Matthew Cannon 1,  Janek S Walker 1,  Daniel Canfield 1,  Larry Beaver 1,  Casey B Cempre 1,  Hannah Phillips 1,  Xuyong Chen 4,  Pearlly Yan 1,  Amy Lehman 5,  Peggy Scherle 6,  Min Wang 6,  Kris Vaddi 6,  Robert Baiocchi 1,  Ruoning Wang 4,  Deepa Sampath 1,  Lapo Alinari 1,  James S Blachly 1 7 8,  Rosa Lapalombella 1 2 8
Affiliations

Affiliations

  • 1 Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
  • 2 College of Pharmacy, The Ohio State University, Columbus, OH, USA.
  • 3 Department of Outcomes and Translational Sciences, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
  • 4 Center for Childhood Cancer and Blood Diseases, Hematology/Oncology and BMT, Abigail Wexner Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA.
  • 5 Center for Biostatistics, The Ohio State University, Columbus, OH, USA.
  • 6 Prelude Therapeutics, Wilmington, DE, USA.
  • 7 Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA.
  • 8 Leukemia Research Program, The Ohio State University James Comprehensive Cancer Center, Columbus, OH, USA.
PMID: 36112677 DOI: 10.1126/sciadv.abp9005
Abstract

Using a genome-wide CRISPR screen, we identified CDK9, DHODH, and PRMT5 as synthetic lethal partners with gilteritinib treatment in fms-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) acute myeloid leukemia (AML) and genetically and pharmacologically validated their roles in gilteritinib sensitivity. The presence of FLT3-ITD is associated with an increase in anaerobic glycolysis, rendering leukemia cells highly sensitive to inhibition of glycolysis. Supportive of this, our data show the enrichment of single guide RNAs targeting 28 glycolysis-related genes upon gilteritinib treatment, suggesting that switching from glycolysis to oxidative phosphorylation (OXPHOS) may represent a metabolic adaption of AML in gilteritinib resistance. CDK9i/FLT3i, DHODHi/FLT3i, and PRMT5i/FLT3i pairs mechanistically converge on OXPHOS and purine biosynthesis blockade, implying that targeting the metabolic functions of these three genes and/or proteins may represent attractive strategies to sensitize AML to gilteritinib treatment. Our findings provide the basis for maximizing therapeutic impact of FLT3-ITD inhibitors and a rationale for a clinical trial of these novel combinations.

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