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Publication Abstract from PubMed

Agents targeting metabolic pathways form the backbone of standard oncology treatments, though a better understanding of differential metabolic dependencies could instruct more rationale-based therapeutic approaches. We performed a chemical biology screen that revealed a strong enrichment in sensitivity to a novel dihydroorotate dehydrogenase (DHODH) inhibitor, AG-636, in cancer cell lines of hematologic versus solid tumor origin. Differential AG-636 activity translated to the in vivo setting, with complete tumor regression observed in a lymphoma model. Dissection of the relationship between uridine availability and response to AG-636 revealed a divergent ability of lymphoma and solid tumor cell lines to survive and grow in the setting of depleted extracellular uridine and DHODH inhibition. Metabolic characterization paired with unbiased functional genomic and proteomic screens pointed to adaptive mechanisms to cope with nucleotide stress as contributing to response to AG-636. These findings support targeting of DHODH in lymphoma and other hematologic malignancies and suggest combination strategies aimed at interfering with DNA damage response pathways.

Selective Vulnerability to Pyrimidine Starvation in Hematologic Malignancies Revealed by AG-636, a Novel Clinical-Stage Inhibitor of Dihydroorotate Dehydrogenase.,McDonald G, Chubukov V, Coco J, Truskowski K, Narayanaswamy R, Choe S, Steadman M, Artin E, Padyana AK, Jin L, Ronseaux S, Locuson C, Fan ZP, Erdmann T, Mann A, Hayes S, Fletcher M, Nellore K, Rao SS, Subramanya H, Kunnam SR, Panigrahi SK, Anthony T, Gopinath S, Sui Z, Nagaraja N, Dang L, Lenz G, Hurov J, Biller SA, Murtie J, Marks KM, Ulanet DB Mol Cancer Ther. 2020 Oct 20. pii: 1535-7163.MCT-20-0550. doi:, 10.1158/1535-7163.MCT-20-0550. PMID:33082276^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.