Evidence map›Paper›PMID 40832297›Full record

ArticlebioRxiv : the preprint server for biology2025

EZH2-TTP-mTORC1 Axis Drives Phenotypic Plasticity and Therapeutic Vulnerability in Lethal Prostate Cancer.

Beatriz German, Katherine L Morel, Teia Noel, Nadia Boufaied, Deborah L Burkhart, Sujun Chen, Felipe Dezem, Xintao Qui, Henry W Long, Stefan DiFazio and 11 more

Abstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in bioRxiv : the preprint server for biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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

0 citing papers in PubMed.

No citing paper in PubMed yet.

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

21 authors.

Beatriz GermanCenter for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.ORCID 0009-0004-5105-4583
Katherine L MorelSouth Australian Immunogenomics Cancer Institute, University of Adelaide, Adelaide SA, Australia.ORCID 0000-0002-7968-4032
Teia NoelCedars-Sinai Center for Bioinformatics and Functional Genomics, Los Angeles CA, USA.ORCID 0000-0001-7084-8902
Nadia BoufaiedCancer Research Program, Research Institute of the McGill University Health Center, Montreal, QC, Canada.ORCID 0000-0002-4533-7155
Deborah L BurkhartDepartment of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston MA, USA.ORCID 0000-0002-7457-6032
Sujun ChenWest China School of Public Health, West China Fourth Hospital, and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China.ORCID 0000-0002-1941-3951
Felipe DezemDepartment of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis TN, USA.ORCID 0009-0001-0363-8515
Xintao QuiCenter for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston MA, USA.ORCID 0000-0002-8560-7017
Henry W LongCenter for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston MA, USA.ORCID 0000-0001-6849-6629
Stefan DiFazioCenter for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
Sylvan BacaDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston MA, USA.ORCID 0000-0002-4087-8606
Ayesha A ShafiCenter for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.ORCID 0000-0003-0335-638X
Matthew L FreedmanCenter for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston MA, USA.
Himisha BeltranDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston MA, USA.ORCID 0000-0003-3259-2226
Christopher J SweeneySouth Australian Immunogenomics Cancer Institute, University of Adelaide, Adelaide SA, Australia.ORCID 0000-0002-0398-6018
Housheng Hansen HePrincess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.ORCID 0000-0003-2898-3363
Myles BrownCenter for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston MA, USA.ORCID 0000-0002-8213-1658
Jasmine T PlummerDepartment of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis TN, USA.ORCID 0000-0001-7263-350X
Simon R V KnottCedars-Sinai Center for Bioinformatics and Functional Genomics, Los Angeles CA, USA.ORCID 0000-0002-4018-7653
David P LabbeCancer Research Program, Research Institute of the McGill University Health Center, Montreal, QC, Canada.ORCID 0000-0001-8864-8765
Leigh EllisCenter for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.ORCID 0000-0003-4739-5049

Funding

ATR Dependency as a Novel Therapeutic Target in Lethal RB Deficient ProstateCancerR01CA252468 · NCI · HENRY M. JACKSON FDN FOR THE ADV MIL/MED · PI Leigh Ellis · 2020 to 2026
$1.5M
NCI NIH HHS R01 CA252468
6 · The paper itself

Abstract

Phenotypic plasticity is a recognized mechanism of therapeutic resistance in prostate cancer (PCa), however current knowledge of driver mechanisms and therapeutic interventions are limited. Using genetically engineered mouse models (GEMMs) devoid of Pten and Rb1, we previously demonstrated the chromatin reprogramming factor enhancer of zeste homolog 2 (EZH2) as an important regulator of alternative transcription programs promoting phenotypic plasticity. Here, using a multi-omics approach we demonstrate that EZH2 regulates multilineage cell states dependent on the RNA binding protein Tristetraprolin (TTP) that mediates RNA stability and activation of translation. Combined chemical inhibition of EZH2 and PI3K/mTORC1 resulted in superior anti-tumor activity in murine and human phenotypic plastic models and was most significant when this combination was used with castration or enzalutamide. Together, these data indicate phenotypic plasticity dependence on coordination between EZH2, TTP and mTORC1 signaling that represent novel therapeutic dependencies for this lethal PCa phenotype.

Indexed as

EZH2mTORPhenotypic PlasticityPI3KTranslation

Identifiers

PMID40832297
PMCPMC12363794

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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.