Replication Stress Is an Actionable Genetic Vulnerability in Desmoplastic Small Round Cell Tumors

Desmoplastic small round cell tumor (DSRCT) is an aggressive sarcoma subtype that is driven by the EWS-WT1 chimeric transcription factor. The prognosis for DSRCT is poor, and major advances in treating DSRCT have not occurred for over two decades. To identify effective therapeutic approaches to target DSRCT, we conducted a high-throughput drug sensitivity screen in a DSRCT cell line assessing chemosensitivity profiles for 79 small-molecule inhibitors. DSRCT cells were sensitive to PARP inhibitors (PARPi) and ataxia-telangiectasia and Rad3-related inhibitors (ATRi), as monotherapies and in combination. These effects were recapitulated using multiple clinical PARPi and ATRi in three biologically distinct, clinically relevant models of DSRCT, including cell lines, a patient-derived xenograft-derived organoid model, and a cell line-derived xenograft mouse model. Mechanistically, exposure to a combination of PARPi and ATRi caused increased DNA damage, G2-M checkpoint activation, micronuclei accumulation, replication stress, and R-loop formation. EWS-WT1 silencing abrogated these phenotypes and was epistatic with exogenous expression of the R-loop resolution enzyme RNase H1 in reversing sensitivity to PARPi and ATRi monotherapies. The combination of PARPi and ATRi also induced EWS-WT1-dependent cell-autonomous activation of the cyclic GMP-AMP synthase-stimulator of IFN genes innate immune pathway and cell-surface expression of PD-L1. Taken together, these findings point toward a role for EWS-WT1 in generating R-loop-dependent replication stress that leads to a targetable vulnerability, providing a rationale for the clinical assessment of PARPi and ATRi in DSRCT. Significance: EWS-WT1, the unique oncogenic driver of desmoplastic small round cell tumors, confers sensitivity to PARP and ATR inhibitors, supporting the potential of these drugs in treating patients with this aggressive sarcoma subtype.

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Publication Details

Journal
Cancer Research
Published
2024-10-16
DOI
https://doi.org/10.1158/0008-5472.can-23-3603
Citations
3
Primary Topic
Sarcoma Diagnosis and Treatment
Type
article
Field-Weighted Citation Impact
1.26

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article

Replication Stress Is an Actionable Genetic Vulnerability in Desmoplastic Small Round Cell Tumors

JANET M. SHIPLEY, Carine Ngo, Oliviano Martella, Sophie C. Postel-Vinay et al.
3 citations
Cancer Research
Sarcoma Diagnosis and Treatment
1.26
article

Replication Stress Is an Actionable Genetic Vulnerability in Desmoplastic Small Round Cell Tumors

JANET M. SHIPLEY, Carine Ngo, Oliviano Martella, Sophie C. Postel-Vinay, Noé Herbel, Rachel Brough, Anastasia Loktev, Matthieu Faron, Julien Vibert, Thomas Eychenne, Asuka Kawachi, Antonio Romo‐Morales, Marjorie Drac, Léo Colmet‐Daage, Clémence Astier, Aditi Gulati, Roman M. Chabanon, Meritxell B. Cutrona, Nicolas Dorvault, Étienne Schwob, Charles Honoré, Guillaume Pinna, Feifei Song, Sibylle Mittnacht, Clémence Henon, Marlène Garrido, Olivier Mir, Astrid Zimmermann, Christopher J. Lord, Axel Le Cesne, Ryme Bouyakoub, Madison M. Lenormand, Laetitia Bordelet
article en
3 citations

Abstract

Desmoplastic small round cell tumor (DSRCT) is an aggressive sarcoma subtype that is driven by the EWS-WT1 chimeric transcription factor. The prognosis for DSRCT is poor, and major advances in treating DSRCT have not occurred for over two decades. To identify effective therapeutic approaches to target DSRCT, we conducted a high-throughput drug sensitivity screen in a DSRCT cell line assessing chemosensitivity profiles for 79 small-molecule inhibitors. DSRCT cells were sensitive to PARP inhibitors (PARPi) and ataxia-telangiectasia and Rad3-related inhibitors (ATRi), as monotherapies and in combination. These effects were recapitulated using multiple clinical PARPi and ATRi in three biologically distinct, clinically relevant models of DSRCT, including cell lines, a patient-derived xenograft-derived organoid model, and a cell line-derived xenograft mouse model. Mechanistically, exposure to a combination of PARPi and ATRi caused increased DNA damage, G2-M checkpoint activation, micronuclei accumulation, replication stress, and R-loop formation. EWS-WT1 silencing abrogated these phenotypes and was epistatic with exogenous expression of the R-loop resolution enzyme RNase H1 in reversing sensitivity to PARPi and ATRi monotherapies. The combination of PARPi and ATRi also induced EWS-WT1-dependent cell-autonomous activation of the cyclic GMP-AMP synthase-stimulator of IFN genes innate immune pathway and cell-surface expression of PD-L1. Taken together, these findings point toward a role for EWS-WT1 in generating R-loop-dependent replication stress that leads to a targetable vulnerability, providing a rationale for the clinical assessment of PARPi and ATRi in DSRCT. Significance: EWS-WT1, the unique oncogenic driver of desmoplastic small round cell tumors, confers sensitivity to PARP and ATR inhibitors, supporting the potential of these drugs in treating patients with this aggressive sarcoma subtype.

Cancer ResearchVol. 85(1)
Université Paris-Sud (FR), Centre National de la Recherche Scientifique (FR), Institute of Cancer Research (GB), Inserm (FR), Institut Pasteur (FR), Merck KGaA, Darmstadt (Germany) (DE), Université de Montpellier (FR), Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR), Université Paris-Saclay (FR), Breast Cancer Now (GB), Institut Gustave Roussy (FR), CEA Paris-Saclay - Etablissement de Fontenay-aux-roses (FR), Institut de Génétique Moléculaire de Montpellier (FR), CEA Paris-Saclay (FR), Hesse (Germany) (DE), CRUK Lung Cancer Centre of Excellence (GB), Institut de Génétique Humaine (FR), University College London (GB), National Cancer Research Institute (GB)
Amgen, AstraZeneca, St. Baldrick's Foundation, Merck KGaA, Turner Foundation, Danish Cancer Society Research Center, Agios Pharmaceuticals, Cancer Research UK, Institut National de la Santé et de la Recherche Médicale, Fondation pour la Recherche Médicale, Fondation ARC pour la Recherche sur le Cancer, Ligue Contre le Cancer, Centre National de la Recherche Scientifique, Institut National Du Cancer, European Society for Medical Oncology, Fondation Bettencourt Schueller, Institut Gustave-Roussy, Direction Générale de l’offre de Soins, Servier, Fondation des Treilles, Institut Servier, CRIS Cancer Foundation
No poverty
Openalex Percentile: Top 18%
Sarcoma Diagnosis and Treatment
1.26
DOIOpen Access PDFOpenAlex
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