Evidence map›Paper›PMID 33987681›Full record

ArticleNeuro-oncology2021

BET inhibitors repress expression of interferon-stimulated genes and synergize with HDAC inhibitors in glioblastoma.

Olga Gusyatiner, Pierre Bady, Minh D T Pham, Yvonne Lei, Jungyeon Park, Roy T Daniel, Mauro Delorenzi, Monika E Hegi

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Neuro-oncology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.

0numbers the graph read from it
0cells of the map it votes in
26citing papers in PubMed
2.8field-weighted citation impact, top 8% of its field
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

26 citing papers in PubMed, 40 citations in OpenAlex.

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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

8 authors at 3 institutions in 1 country.

Olga GusyatinerNeuroscience Research Centre, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
Pierre BadyNeuroscience Research Centre, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.ORCID 0000-0003-1398-4689
Minh D T PhamNeuroscience Research Centre, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
Yvonne LeiNeuroscience Research Centre, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
Jungyeon ParkNeuroscience Research Centre, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
Roy T DanielService of Neurosurgery, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
Mauro DelorenziBioinformatics Core Facility, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.
Monika E HegiService of Neurosurgery, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.ORCID 0000-0003-0855-6495
University of Lausanne · CHSIB Swiss Institute of Bioinformatics · CHSwiss Cancer Center Léman · CH

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundThe development of rational combination therapies is key to overcome inherent treatment resistance of glioblastoma (GBM). We aim at identifying new druggable targets by disturbing GBM cells with inhibitors of bromodomain and extra-terminal motif (BET) proteins to reveal cancer-relevant vulnerabilities that may sensitize to a second drug. BET proteins are epigenetic modulators and have been associated with proto-oncogene overexpression in cancer.

methodsA GBM-derived sphere-line was treated with the BET inhibitor (BETi) JQ1 over a time-course of 48 hours, followed by RNA-sequencing. Four chromatin marks were investigated by chromatin immunoprecipitation followed by sequencing (ChIP-seq). Signatures of interest were functionally validated in vitro and in orthotopic xenografts. Combination therapies were evaluated for synergistic effects.

resultsCancer-relevant pathways significantly modulated by JQ1 comprised interferon alpha (IFN-α) response genes and response signatures to histone deacetylase inhibitors (HDACi). The IFN-signature was reminiscent of a GBM-derived IFN-signature comprising CD274 (PD-L1). Functional pathway analysis suggested that JQ1 was acting directly on the transcriptional level of IFN-response genes and not via the canonical JAK/STAT pathway. This was in line with JQ1 modulated expression and BRD4 and Pol II occupancy at IFN-signature genes, supporting a direct mechanistic interaction. Finally, we showed that combining HDACi with JQ1 acts synergistically in reducing cell viability of GS-lines.

conclusionsOur approach identified BETi-induced vulnerabilities in cancer-relevant pathways, potentially amenable to synergistic combinatorial therapy, such as combination with HDACi. The direct inhibitory effect of BETi on IFN-responsive genes in GBM cells, including CD274, indicates modulation of the tumor immune landscape and warrants further studies.

Indexed as

GlioblastomaHistone Deacetylase InhibitorsHumansInterferonsNuclear ProteinsProto-Oncogene MasHistone Deacetylase InhibitorsInterferonsMAS1 protein, humanNuclear ProteinsProto-Oncogene MasBET inhibitorsepigeneticsglioblastomainterferon-stimulated genessynergistic combination therapy

Identifiers

PMID33987681
PMCPMC8485441
OpenAlexW3163034601

What OpenQuestion holds

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Registered trials

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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.