TY - JOUR
T1 - Replication Stress Is an Actionable Genetic Vulnerability in Desmoplastic Small Round Cell Tumors
AU - Kawai-Kawachi, Asuka
AU - Lenormand, Madison M.
AU - Astier, Clémence
AU - Herbel, Noé
AU - Cutrona, Meritxell B.
AU - Ngo, Carine
AU - Garrido, Marlène
AU - Eychenne, Thomas
AU - Dorvault, Nicolas
AU - Bordelet, Laetitia
AU - Song, Feifei
AU - Bouyakoub, Ryme
AU - Loktev, Anastasia
AU - Romo-Morales, Antonio
AU - Henon, Clémence
AU - Colmet-Daage, Léo
AU - Vibert, Julien
AU - Drac, Marjorie
AU - Brough, Rachel
AU - Schwob, Etienne
AU - Martella, Oliviano
AU - Pinna, Guillaume
AU - Shipley, Janet M.
AU - Mittnacht, Sibylle
AU - Zimmermann, Astrid
AU - Gulati, Aditi
AU - Mir, Olivier
AU - Le Cesne, Axel
AU - Faron, Matthieu
AU - Honoré, Charles
AU - Lord, Christopher J.
AU - Chabanon, Roman M.
AU - Postel-Vinay, Sophie
N1 - Publisher Copyright:
©2024 The Authors; Published by the American Association for Cancer Research.
PY - 2025/1/1
Y1 - 2025/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85214320536&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-23-3603
DO - 10.1158/0008-5472.CAN-23-3603
M3 - Article
C2 - 39412947
AN - SCOPUS:85214320536
SN - 0008-5472
VL - 85
SP - 154
EP - 170
JO - Cancer Research
JF - Cancer Research
IS - 1
ER -