Journal article
Cell Context is the third axis of synergy for the combination of ATR inhibition and cisplatin in Ewing sarcoma
Clinical cancer research, Vol.30(16), pp.3533-3548
03/20/2024
DOI: 10.1158/1078-0432.CCR-23-3063
PMID: 38506712
Abstract
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 (ES).
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 ES selectivity, and optimized for in vivo schedule.
Berzosertib combined with cisplatin demonstrates profound synergy in multiple ES cell lines at clinically achievable concentrations. The synergy is due to loss of expression of the ATR downstream target CHEK1, loss of cell cycle checkpoints, 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 ES models leading to durable complete responses in 50% of animals bearing two different ES xenografts.
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.
Details
- Title: Subtitle
- Cell Context is the third axis of synergy for the combination of ATR inhibition and cisplatin in Ewing sarcoma
- Creators
- Jennifer Jess - Van Andel InstituteKathleen M Sorensen - Van Andel InstituteElissa A Boguslawski - Children's Hospital of PhiladelphiaMatthew C Stout - Children's Hospital of PhiladelphiaZachary B Madaj - Van Andel InstituteBenjamin P Caiello - University of PennsylvaniaMonica Pomaville - University of ChicagoElizabeth R Wilson - Children's Hospital of PhiladelphiaSeneca S Kinn-Gurzo - Children's Hospital of PhiladelphiaCurtis C Parker - Children's Hospital of PhiladelphiaSridhar M Veluvolu - Children's Hospital of PhiladelphiaTaylor V Brysgel - University of PennsylvaniaRebecca Kaufman - Children's Hospital of PhiladelphiaSusan M Kitchen-Goosen - Van Andel InstituteJenna M Gedminas - University of IowaPatrick J Grohar - Children's Hospital of Philadelphia
- Resource Type
- Journal article
- Publication Details
- Clinical cancer research, Vol.30(16), pp.3533-3548
- Publisher
- AMER ASSOC CANCER RESEARCH
- DOI
- 10.1158/1078-0432.CCR-23-3063
- PMID
- 38506712
- ISSN
- 1078-0432
- eISSN
- 1557-3265
- Grant note
- Merck KGaA: M9831
This work was supported by internal funds from the Van Andel Institute and the Children's Hospital of Philadelphia. The authors would like to thank Vertex Pharmaceuticals and Merck KGaA for providing berzosertib and M9831. We would also like to thank the Children's Hospital of Philadelphia Flow Cytometry Core Laboratory for their expertise and guidance.
- Language
- English
- Electronic publication date
- 03/20/2024
- Academic Unit
- Stead Family Department of Pediatrics; Hematology/Oncology
- Record Identifier
- 9984573950502771
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