Cell Context Is the Third Axis of Synergy for the Combination of ATR Inhibition and Cisplatin in Ewing Sarcoma.

Autor:	Jess J; Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan., Sorensen KM; Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan., Boguslawski EA; Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan.; Division of Oncology, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania., Stout MC; Division of Oncology, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania., Madaj ZB; Bioinformatics and Biostatistics Core, Van Andel Research Institute, Grand Rapids, Michigan., Caiello BP; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Pomaville M; Division of Oncology, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania., Wilson ER; Division of Oncology, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania., Kinn-Gurzo SS; Division of Oncology, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania., Parker CC; Division of Oncology, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania., Veluvolu SM; Division of Oncology, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania., Brysgel TV; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Kaufman R; Division of Oncology, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania., Kitchen-Goosen SM; Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan., Gedminas JM; Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan.; Division of Oncology, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania., Grohar PJ; Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan.; Division of Oncology, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2024 Aug 15; Vol. 30 (16), pp. 3533-3548.
DOI:	10.1158/1078-0432.CCR-23-3063
Abstrakt:	Purpose: The importance of cellular context to the synergy of DNA damage response (DDR)-targeted agents is important for tumors with mutations in DDR pathways, but less well-established for tumors driven by oncogenic transcription factors. In this study, we exploit the widespread transcriptional dysregulation of the EWS-FLI1 transcription factor to identify an effective DDR-targeted combination therapy for Ewing sarcoma. Experimental Design: We used matrix drug screening to evaluate synergy between a DNA-PK inhibitor (M9831) or an ATR inhibitor (berzosertib) and chemotherapy. The combination of berzosertib and cisplatin was selected for broad synergy, mechanistically evaluated for Ewing sarcoma selectivity, and optimized for in vivo schedule. Results: Berzosertib combined with cisplatin demonstrates profound synergy in multiple Ewing sarcoma cell lines at clinically achievable concentrations. The synergy is due to loss of expression of the ATR downstream target CHEK1, loss of cell-cycle check-points, and mitotic catastrophe. Consistent with the goals of the project, EWS-FLI1 drives the expression of CHEK1 and five other ATR pathway members. The loss of CHEK1 expression is not due to transcriptional repression and instead caused by degradation coupled with suppression of protein translation. The profound synergy is realized in vivo with a novel optimized schedule of this combination in subsets of Ewing sarcoma models, leading to durable complete responses in 50% of animals bearing two different Ewing sarcoma xenografts. Conclusions: These data exploit EWS-FLI1 driven alterations in cell context to broaden the therapeutic window of berzosertib and cisplatin to establish a promising combination therapy and a novel in vivo schedule. See related commentary by Ohmura and Grünewald, p. 3358. (©2024 American Association for Cancer Research.)
Databáze:	MEDLINE
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