| Autor: |
Kawai-Kawachi A; National Cancer Centre, Tokyo, Japan., Lenormand MM; Institut Pasteur, Paris, France., Astier C; Institut Gustave Roussy, Villejuif, France., Herbel N; Institut Gustave Roussy, Villejuif, France., Cutrona MB; Institut Gustave Roussy, Villejuif, France., Ngo C; Institut Gustave Roussy, France., Garrido M; Institut Gustave Roussy, Villejuif, France., Eychenne T; Institut Gustave Roussy, Villejuif, France., Dorvault N; Institut Gustave Roussy, Villejuif, France., Bordelet L; Institut Gustave Roussy, France., Song FF; Institute of Cancer Research, London, United Kingdom., Bouyakoub R; Institut Gustave Roussy, Villejuif, Ile de France, France., Loktev A; Institute of Cancer Research, United Kingdom., Romo-Morales A; Institute of Cancer Research, Sutton, Surrey, United Kingdom., Henon C; Institut Gustave Roussy, Villejuif, France., Colmet-Daage L; Institut Gustave Roussy, Villejuif, France., Vibert J; Gustave Roussy, France., Drac M; University of Montpellier, Montpellier, France., Brough R; Institute of Cancer Research, London, United Kingdom., Schwob E; University of Montpellier, Montpellier, France., Martella O; Institut Gustave Roussy, France., Pinna G; CEA Saclay, FONTENAY-AUX-ROSES, France., Shipley JM; Institute of Cancer Research, Sutton, Surrey, United Kingdom., Mittnacht S; University College London, London, United Kingdom., Zimmermann A; Merck (Germany), Darmstadt, Hessen, Germany., Gulati A; Institute of Cancer Research, London, United Kingdom., Mir O; Gustave Roussy Cancer Institute, Villejuif, France., Le Cesne A; Gustave Roussy Cancer Campus, Villejuif, France., Faron M; Institut Gustave Roussy, France., Honoré C; Gustave Roussy Cancer Institute, Villejuif, France., Lord CJ; Institute of Cancer Research, London, United Kingdom., Chabanon RM; Institut Gustave Roussy, Villejuif, France., Postel-Vinay S; Institut Gustave Roussy, Villejuif, France. |
| Abstrakt: |
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 DSCRT 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 and ATR inhibitors (PARPi, 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 (PDX)-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 the sensitivity to PARPi and ATRi monotherapies. The combination of PARPi and ATRi also induced EWS-WT1-dependent cell-autonomous activation of the cGAS/STING innate immune pathway and cell surface expression of PD-L1. Taken together, these findings point towards 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. |
