Combined Targeting of de novo Pyrimidine Synthesis and ATR Promotes ATF4-Mediated Cell Death in TP53-Deficient ALL

Due to their highly proliferative state, ALL cells are strongly dependent on nucleotide synthesis. Inhibitors of dihydroorotate dehydrogenase (DHODH), a pivotal enzyme in de novo pyrimidine biosynthesis, have demonstrated promising single-agent efficacy in some ALL and acute myeloid leukemia (AML) preclinical models.

Using both isogenic TP53 cell line models and patient-derived xenografts (PDX), we show that dual inhibition of DHODH and Ataxia telangiectasia and Rad3 related (ATR) produces pronounced anti-leukemic effects, irrespective of the TP53 status. Through integrated transcriptomic and metabolomic analyses, we show that combined inhibition of DHODH and ATR leads to a reduced flux of glucose to the TCA cycle, accompanied by an increase in oxidative stress.