2. Academic Validation
  3. Selective Vulnerability to Pyrimidine Starvation in Hematologic Malignancies Revealed by AG-636, a Novel Clinical-Stage Inhibitor of Dihydroorotate Dehydrogenase

Selective Vulnerability to Pyrimidine Starvation in Hematologic Malignancies Revealed by AG-636, a Novel Clinical-Stage Inhibitor of Dihydroorotate Dehydrogenase

  • Mol Cancer Ther. 2020 Dec;19(12):2502-2515. doi: 10.1158/1535-7163.MCT-20-0550.
Gabrielle McDonald 1,  Victor Chubukov 2,  John Coco 2,  Kevin Truskowski 2,  Rohini Narayanaswamy 2,  Sung Choe 2,  Mya Steadman 2,  Erin Artin 2,  Anil K Padyana 2,  Lei Jin 2,  Sebastien Ronseaux 2,  Charles Locuson 2,  Zi-Peng Fan 2,  Tabea Erdmann 3,  Alan Mann 2,  Sebastian Hayes 2,  Mark Fletcher 2,  Kavitha Nellore 4,  Siva Sanjeeva Rao 5,  Hosahalli Subramanya 4,  K Satish Reddy 6,  Sunil K Panigrahi 4,  Thomas Antony 4,  Sreevalsam Gopinath 4,  Zhihua Sui 2,  Nelamangala Nagaraja 2,  Lenny Dang 2,  Georg Lenz 3,  Jonathan Hurov 2,  Scott A Biller 2,  Josh Murtie 2,  Kevin M Marks 2,  Danielle B Ulanet 1
Affiliations

Affiliations

  • 1 Agios Pharmaceuticals, Inc., Cambridge, Massachusetts. dulanet@reparerx.com Gabrielle.McDonald@agios.com.
  • 2 Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
  • 3 Department of Medicine A for Hematology, Oncology, and Pneumology, Universitätsklinikum Münster, Münster, Germany.
  • 4 Aurigene Discovery Technologies Ltd., Bangalore, India.
  • 5 Firmus Laboratories, Hyderabad, India.
  • 6 GVK Biosciences, Inc.
PMID: 33082276 DOI: 10.1158/1535-7163.MCT-20-0550
Abstract

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.

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