Evidence map›Paper›PMID 40738904›Full record

ArticleNature communications2025

De novo pyrimidine biosynthesis inhibition synergizes with BCL-X

Huan Zhang, Naiara Santana-Codina, Qijia Yu, Clara Poupault, Claudia Campos, Xingping Qin, Nicole Sindoni, Marina Ciscar, Aparna Padhye, Miljan Kuljanin and 7 more

Abstract read
In one paragraph

Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.

0numbers the graph read from it
0cells of the map it votes in
10citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

10 citing papers in PubMed.

  1. Article
  2. Review
  3. Article
  4. Article
  5. Review
  6. Organoids for disease modeling and treatment: state-of-the-art.Experimental hematology & oncology · 2026
    Review
  7. Article
  8. Review
  9. Article
  10. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

17 authors.

Huan Zhang *Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Naiara Santana-Codina *Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. nsc@biomed.au.dk.ORCID http://orcid.org/0000-0002-8250-4530
Qijia Yu *Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Clara PoupaultDivision of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0003-3145-9773
Claudia CamposDivision of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Xingping QinJohn B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA.ORCID http://orcid.org/0000-0003-3263-0843
Nicole SindoniDivision of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0009-0005-1450-8221
Marina CiscarDepartment of Biomedicine, Aarhus University, Aarhus, Denmark.
Aparna PadhyeDivision of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Miljan KuljaninDivision of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Junning WangDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Matthew J DormanDivision of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Peter BrossResearch Unit for Molecular Medicine, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.ORCID http://orcid.org/0000-0001-9526-8525
Andrew J AguirreDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0002-0701-6203
Stephanie K DouganDepartment of Immunology, Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0002-2263-363X
Kristopher A SarosiekJohn B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA.ORCID http://orcid.org/0000-0002-4618-5085
Joseph D ManciasDivision of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. Joseph_Mancias@dfci.harvard.edu.ORCID http://orcid.org/0000-0002-0692-3717

Funding

Developmental regulation of apoptosis as a modifiable driver of radiotherapy-induced neurocognitive impairment in pediatric patientsR37CA248565 · NCI · HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH · PI Kristopher Andrew Sarosiek · 2020 to 2026
$2.6M
Mechanisms of response and resistance to KRAS inhibition in pancreatic cancerR01CA276268 · NCI · DANA-FARBER CANCER INST · PI Andrew James Aguirre · 2023 to 2026
$2.2M
Identifying targetable apoptotic vulnerabilities for the treatment of AL amyloidosisR01DK125263 · NIDDK · HARVARD SCHOOL OF PUBLIC HEALTH · PI SAROSIEK, KRISTOPHER ANDREW · 2020 to 2023
$1.4M
NCI NIH HHS R01 CA276268NCI NIH HHS R37 CA248565NIDDK NIH HHS R01 DK125263
6 · The paper itself

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-X

Indexed as

bcl-X ProteinCarcinoma, Pancreatic DuctalOxidoreductases Acting on CH-CH Group DonorsPancreatic NeoplasmsPyrimidinesAnimalsApoptosisBiphenyl CompoundsCell Line, TumorDihydroorotate DehydrogenaseDrug SynergismHumansMiceProteomicsQuinaldinesXenograft Model Antitumor AssaysBCL2L1 protein, humanbcl-X ProteinBiphenyl CompoundsbrequinarDihydroorotate DehydrogenaseOxidoreductases Acting on CH-CH Group DonorspyrimidinePyrimidinesQuinaldines

Identifiers

PMID40738904
PMCPMC12311037

What Socratic holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.