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

• DOI: 10.1126/sciadv.abp9005
• Publication Date: 2022-09-16T17:58:17Z
• Authors: Pu Zhang; Lindsey T. Brinton; Mehdi Gharghabi; Steven Sher; Katie Williams; Matthew Cannon; Janek S. Walker; Daniel Canfield; Larry Beaver; Casey B. Cempre; Hannah Phillips; Xuyong Chen; Pearlly Yan; Amy Lehman; Peggy Scherle; Min Wang; Kris Vaddi; Robert Baiocchi; Ruoning Wang; Deepa Sampath; Lapo Alinari; James S. Blachly; Rosa Lapalombella
• Keywords: 0301 basic medicine; 03 medical and health sciences; Biomedicine and Life Sciences; 3. Good health

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) genetically pharmacologically validated their roles sensitivity. The presence of -ITD is associated an increase anaerobic glycolysis, rendering cells highly sensitive to inhibition glycolysis. Supportive this, our data show the enrichment single guide RNAs targeting 28 glycolysis-related genes upon treatment, suggesting that switching from glycolysis oxidative phosphorylation (OXPHOS) may represent metabolic adaption AML resistance. CDK9i/FLT3i, DHODHi/FLT3i, PRMT5i/FLT3i pairs mechanistically converge on OXPHOS purine biosynthesis blockade, implying functions these three and/or proteins attractive strategies sensitize treatment. Our findings provide basis for maximizing therapeutic impact inhibitors rationale clinical trial novel combinations.