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

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

    Résultats de recherche: Contribution à un journalArticleRevue par des pairs

    Résumé

    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 chemo-sensitivity 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.

    langue originaleAnglais
    Pages (de - à)154-170
    Nombre de pages17
    journalCancer Research
    Volume85
    Numéro de publication1
    Les DOIs
    étatPublié - 1 janv. 2025

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