Evidence map›Paper›PMID 39332586›Full record

ArticleCancer letters2024

Integration of transcriptomics, proteomics and loss-of-function screening reveals WEE1 as a target for combination with dasatinib against proneural glioblastoma.

Obada T Alhalabi, Mona Göttmann, Maxwell P Gold, Silja Schlue, Thomas Hielscher, Murat Iskar, Tobias Kessler, Ling Hai, Tolga Lokumcu, Clara C Cousins and 13 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cancer letters, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.

0numbers the graph read from it
0cells of the map it votes in
6citing 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

6 citing papers in PubMed.

  1. Article
  2. Review
  3. Article
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  5. Review
  6. 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

23 authors.

Obada T AlhalabiBrain Tumor Translational Targets, DKFZ Junior Group, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany.
Mona GöttmannBrain Tumor Translational Targets, DKFZ Junior Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Maxwell P GoldDepartment of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA.
Silja SchlueBrain Tumor Translational Targets, DKFZ Junior Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Thomas HielscherDivision of Biostatistics (C060), German Cancer Research Center, Germany.
Murat IskarDivision of Molecular Genetics, Heidelberg Center for Personalized Oncology, German Cancer Research Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Tobias KesslerClinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Neurology and Neurooncology Program, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany.
Ling HaiDepartment of Neurology and Neurooncology Program, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany.
Tolga LokumcuBrain Tumor Translational Targets, DKFZ Junior Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Clara C CousinsDepartment of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA.
Christel Herold-MendeDivision of Experimental Neurosurgery, Department of Neurosurgery, Heidelberg University Hospital, 69120, Heidelberg, Germany.
Bernd HeßlingGenomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Sandra HorschitzCentral Institute of Mental Health, University of Heidelberg/Medical Faculty Mannheim, Mannheim, Germany; Hector Institute for Translational Brain Research (HITBR gGmbH), Mannheim, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
Ammar JabaliCentral Institute of Mental Health, University of Heidelberg/Medical Faculty Mannheim, Mannheim, Germany; Hector Institute for Translational Brain Research (HITBR gGmbH), Mannheim, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
Philipp KochCentral Institute of Mental Health, University of Heidelberg/Medical Faculty Mannheim, Mannheim, Germany; Hector Institute for Translational Brain Research (HITBR gGmbH), Mannheim, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
Ulrich BaumgartnerCell and Molecular Biology Department, QIMR Berghofer Medical Research Institute, Sid Faithfull Brain Cancer Laboratory, Brisbane, QLD, 4006, Australia; School of Biomedical Sciences, The University of Queensland, Brisbane, 4072, Australia.
Bryan W DayCell and Molecular Biology Department, QIMR Berghofer Medical Research Institute, Sid Faithfull Brain Cancer Laboratory, Brisbane, QLD, 4006, Australia; School of Biomedical Sciences, The University of Queensland, Brisbane, 4072, Australia.
Wolfgang WickClinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Neurology and Neurooncology Program, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany.
Felix SahmDepartment of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
Sandro M KriegDepartment of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany.
Ernest FraenkelDepartment of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA; Eli and Edythe Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Emma PhillipsBrain Tumor Translational Targets, DKFZ Junior Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Violaine GoidtsBrain Tumor Translational Targets, DKFZ Junior Group, German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address: v.goidts@dkfz.de.

Funding

Graduate Training in Computational and Systems BiologyT32GM087237 · NIGMS · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI BURGE, CHRISTOPHER B · 2009 to 2023
$4.6M
Identifying therapeutic pathways targeting medulloblastoma-immune cell interactionsU01CA253547 · NCI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI FRAENKEL, ERNEST, MESIROV, JILL P. · 2021 to 2025
$2.7M
NCI NIH HHS U01 CA253547NIGMS NIH HHS T32 GM087237
6 · The paper itself

Abstract

Glioblastoma is characterized by a pronounced resistance to therapy with dismal prognosis. Transcriptomics classify glioblastoma into proneural (PN), mesenchymal (MES) and classical (CL) subtypes that show differential resistance to targeted therapies. The aim of this study was to provide a viable approach for identifying combination therapies in glioblastoma subtypes. Proteomics and phosphoproteomics were performed on dasatinib inhibited glioblastoma stem cells (GSCs) and complemented by an shRNA loss-of-function screen to identify genes whose knockdown sensitizes GSCs to dasatinib. Proteomics and screen data were computationally integrated with transcriptomic data using the SamNet 2.0 algorithm for network flow learning to reveal potential combination therapies in PN GSCs. In vitro viability assays and tumor spheroid models were used to verify the synergy of identified therapy. Further in vitro and TCGA RNA-Seq data analyses were utilized to provide a mechanistic explanation of these effects. Integration of data revealed the cell cycle protein WEE1 as a potential combination therapy target for PN GSCs. Validation experiments showed a robust synergistic effect through combination of dasatinib and the WEE1 inhibitor, MK-1775, in PN GSCs. Combined inhibition using dasatinib and MK-1775 propagated DNA damage in PN GCSs, with GCSs showing a differential subtype-driven pattern of expression of cell cycle genes in TCGA RNA-Seq data. The integration of proteomics, loss-of-function screens and transcriptomics confirmed WEE1 as a target for combination with dasatinib against PN GSCs. Utilizing this integrative approach could be of interest for studying resistance mechanisms and revealing combination therapy targets in further tumor entities.

Indexed as

Cell Cycle ProteinsDasatinibGlioblastomaProtein-Tyrosine KinasesProteomicsPyrazolesPyrimidinesAntineoplastic Combined Chemotherapy ProtocolsBrain NeoplasmsCell Line, TumorDrug SynergismGene Expression ProfilingGene Expression Regulation, NeoplasticHumansNeoplastic Stem CellsProtein Kinase InhibitorsadavosertibCell Cycle ProteinsDasatinibProtein Kinase InhibitorsProtein-Tyrosine KinasesPyrazolesPyrimidinesPyrimidinonesWEE1 protein, humanComputational integrationDasatinibLoss-of-function shRNA screenPhosphoproteomicsWEE1

Identifiers

PMID39332586
PMCPMC12768573

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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 OpenQuestion graph.