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Molecular Cancer Therapeutics
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Small Molecule Therapeutics

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

Gabrielle McDonald, Victor Chubukov, John Coco, Kevin Truskowski, Rohini Narayanaswamy, Sung Choe, Mya Steadman, Erin Artin, Anil K. Padyana, Lei Jin, Sebastien Ronseaux, Charles Locuson, Zi-Peng Fan, Tabea Erdmann, Alan Mann, Sebastian Hayes, Mark Fletcher, Kavitha Nellore, Siva Sanjeeva Rao, Hosahalli Subramanya, K. Satish Reddy, Sunil K. Panigrahi, Thomas Antony, Sreevalsam Gopinath, Zhihua Sui, Nelamangala Nagaraja, Lenny Dang, Georg Lenz, Jonathan Hurov, Scott A. Biller, Josh Murtie, Kevin M. Marks and Danielle B. Ulanet
Gabrielle McDonald
1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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  • For correspondence: dulanet@reparerx.com Gabrielle.McDonald@agios.com
Victor Chubukov
1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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John Coco
1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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Kevin Truskowski
1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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  • ORCID record for Kevin Truskowski
Rohini Narayanaswamy
1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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Sung Choe
1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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Mya Steadman
1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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Erin Artin
1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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Anil K. Padyana
1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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Lei Jin
1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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  • ORCID record for Lei Jin
Sebastien Ronseaux
1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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Charles Locuson
1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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Zi-Peng Fan
1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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Tabea Erdmann
2Department of Medicine A for Hematology, Oncology, and Pneumology, Universitätsklinikum Münster, Münster, Germany.
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Alan Mann
1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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Sebastian Hayes
1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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Mark Fletcher
1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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Kavitha Nellore
3Aurigene Discovery Technologies Ltd., Bangalore, India.
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Siva Sanjeeva Rao
4Firmus Laboratories, Hyderabad, India.
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Hosahalli Subramanya
3Aurigene Discovery Technologies Ltd., Bangalore, India.
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K. Satish Reddy
5GVK Biosciences, Inc.
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Sunil K. Panigrahi
3Aurigene Discovery Technologies Ltd., Bangalore, India.
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Thomas Antony
3Aurigene Discovery Technologies Ltd., Bangalore, India.
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Sreevalsam Gopinath
3Aurigene Discovery Technologies Ltd., Bangalore, India.
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Zhihua Sui
1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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Nelamangala Nagaraja
1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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Lenny Dang
1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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Georg Lenz
2Department of Medicine A for Hematology, Oncology, and Pneumology, Universitätsklinikum Münster, Münster, Germany.
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Jonathan Hurov
1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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Scott A. Biller
1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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Josh Murtie
1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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Kevin M. Marks
1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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Danielle B. Ulanet
1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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  • For correspondence: dulanet@reparerx.com Gabrielle.McDonald@agios.com
DOI: 10.1158/1535-7163.MCT-20-0550 Published December 2020
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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.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Mol Cancer Ther 2020;19:2502–15

  • Received July 1, 2020.
  • Revision received September 20, 2020.
  • Accepted September 25, 2020.
  • Published first October 20, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 19 (12)
December 2020
Volume 19, Issue 12
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Selective Vulnerability to Pyrimidine Starvation in Hematologic Malignancies Revealed by AG-636, a Novel Clinical-Stage Inhibitor of Dihydroorotate Dehydrogenase
Gabrielle McDonald, Victor Chubukov, John Coco, Kevin Truskowski, Rohini Narayanaswamy, Sung Choe, Mya Steadman, Erin Artin, Anil K. Padyana, Lei Jin, Sebastien Ronseaux, Charles Locuson, Zi-Peng Fan, Tabea Erdmann, Alan Mann, Sebastian Hayes, Mark Fletcher, Kavitha Nellore, Siva Sanjeeva Rao, Hosahalli Subramanya, K. Satish Reddy, Sunil K. Panigrahi, Thomas Antony, Sreevalsam Gopinath, Zhihua Sui, Nelamangala Nagaraja, Lenny Dang, Georg Lenz, Jonathan Hurov, Scott A. Biller, Josh Murtie, Kevin M. Marks and Danielle B. Ulanet
Mol Cancer Ther December 1 2020 (19) (12) 2502-2515; DOI: 10.1158/1535-7163.MCT-20-0550

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Selective Vulnerability to Pyrimidine Starvation in Hematologic Malignancies Revealed by AG-636, a Novel Clinical-Stage Inhibitor of Dihydroorotate Dehydrogenase
Gabrielle McDonald, Victor Chubukov, John Coco, Kevin Truskowski, Rohini Narayanaswamy, Sung Choe, Mya Steadman, Erin Artin, Anil K. Padyana, Lei Jin, Sebastien Ronseaux, Charles Locuson, Zi-Peng Fan, Tabea Erdmann, Alan Mann, Sebastian Hayes, Mark Fletcher, Kavitha Nellore, Siva Sanjeeva Rao, Hosahalli Subramanya, K. Satish Reddy, Sunil K. Panigrahi, Thomas Antony, Sreevalsam Gopinath, Zhihua Sui, Nelamangala Nagaraja, Lenny Dang, Georg Lenz, Jonathan Hurov, Scott A. Biller, Josh Murtie, Kevin M. Marks and Danielle B. Ulanet
Mol Cancer Ther December 1 2020 (19) (12) 2502-2515; DOI: 10.1158/1535-7163.MCT-20-0550
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