Nicole Sindoni
Current Organizations / Institutes
The organizations/institutes from the scholar's latest article
Nicole Sindoni has a total of 16 co-authors. Here are the top co-authors by number of shared publications:
- Andrew J. Aguirre
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
1 shared publication Aparna Padhye
Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA
1 shared publication- Clara Poupault
Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA
1 shared publication Claudia Campos
Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA
1 shared publicationHuan Zhang
Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA
1 shared publication- Joseph D. Mancias
Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA
1 shared publication
Latest Publications
- Open Access
- 30 July 2025
- Published by Springer Nature in Nature Communications
- Vol. 16 (1) , 1-18
De novo pyrimidine biosynthesis inhibition synergizes with BCL-XL targeting in pancreatic cancer
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.
- 30 July 2025
- Published by Springer Nature in Nature Communications
- Vol. 16 (1) , 1-18
Open AccessDe novo pyrimidine biosynthesis inhibition synergizes with BCL-XL targeting in pancreatic cancer
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.