De novo pyrimidine biosynthesis inhibition synergizes with BCL-XL targeting in pancreatic cancer

Huan Zhang, Naiara Santana-Codina (), Qijia Yu, Clara Poupault, Claudia Campos, Xingping Qin, Nicole Sindoni, Marina Ciscar, Aparna Padhye, Miljan Kuljanin, Junning Wang, Matthew J. Dorman, Peter Bross, Andrew J. Aguirre, Stephanie K. Dougan, Kristopher A. Sarosiek and Joseph D. Mancias ()
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Huan Zhang: Harvard Medical School
Naiara Santana-Codina: Harvard Medical School
Qijia Yu: Harvard Medical School
Clara Poupault: Harvard Medical School
Claudia Campos: Harvard Medical School
Xingping Qin: Harvard T.H. Chan School of Public Health
Nicole Sindoni: Harvard Medical School
Marina Ciscar: Aarhus University
Aparna Padhye: Harvard Medical School
Miljan Kuljanin: Harvard Medical School
Junning Wang: Harvard Medical School
Matthew J. Dorman: Harvard Medical School
Peter Bross: Aarhus University
Andrew J. Aguirre: Harvard Medical School
Stephanie K. Dougan: Harvard Medical School
Kristopher A. Sarosiek: Harvard T.H. Chan School of Public Health
Joseph D. Mancias: Harvard Medical School

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Oncogenic KRAS induces metabolic rewiring in pancreatic ductal adenocarcinoma (PDAC) characterized, in part, by dependency on de novo pyrimidine biosynthesis. Pharmacologic inhibition of dihydroorotate dehydrogenase (DHODH), an enzyme in the de novo pyrimidine synthesis pathway, delays pancreatic tumor growth; however, limited monotherapy efficacy suggests that compensatory pathways may drive resistance. Here, we use an integrated metabolomic, proteomic and in vitro and in vivo DHODH inhibitor-anchored genetic screening approach to identify compensatory pathways to DHODH inhibition (DHODHi) and targets for combination therapy strategies. We demonstrate that DHODHi alters the apoptotic regulatory proteome thereby enhancing sensitivity to inhibitors of the anti-apoptotic BCL2L1 (BCL-XL) protein. Co-targeting DHODH and BCL-XL synergistically induces apoptosis in PDAC cells and patient-derived organoids. The combination of DHODH inhibition with Brequinar and BCL-XL degradation by DT2216, a proteolysis targeting chimera (PROTAC), significantly inhibits PDAC tumor growth. These data define mechanisms of adaptation to DHODHi and support combination therapy targeting BCL-XL in PDAC.

Date: 2025
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DOI: 10.1038/s41467-025-61242-x

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