DHODH: A promising target in the treatment of T-Acute Lymphoblastic Leukemia.

Patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) have a poor prognosis with few therapeutic options. With the goal of identifying novel therapeutic targets, we used data from the Dependency Map project to identify DHODH (dihydroorotate dehydrogenase) as one of the top metabolic dependencies in T-ALL. DHODH catalyzes the fourth step of de novo pyrimidine nucleotide synthesis. Small molecule inhibition of DHODH rapidly leads to the depletion of intracellular pyrimidine pools and forces cells to rely on extracellular salvage. In the absence of sufficient salvage, this intracellular nucleotide starvation results in the inhibition of DNA and RNA synthesis, cell cycle arrest, and ultimately death. T lymphoblasts appear to be specifically and exquisitely sensitive to nucleotide starvation following DHODHi. We have confirmed this sensitivity in vitro as well as in vivo in three murine models of T ALL. We identified that certain subsets of T-ALL seem to have an increased reliance on oxidative phosphorylation when treated with DHODHi. Through a series of metabolic assays, we show that leukemia cells, in the setting of nucleotide starvation, have changes in their mitochondrial membrane potential and may be more highly dependent on alternative fuel sources. The effect on normal T cell development in young mice was also examined to show that DHODH inhibition does not permanent damage the developing thymus. These changes suggest a new metabolic vulnerability that may distinguish these cells from normal T-cells and other normal hematopoietic cells and offer an exploitable therapeutic opportunity. The availability of clinical-grade DHODH inhibitors currently in human clinical trials speaks to the potential for rapidly advancing this work into the clinic.