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

• DOI: 10.1158/1078-0432.c.7403523.v1
• Publication Date: 2024-08-15T07:31:02Z
• Authors: Jennifer Jess; Katie M. Sorensen; Elissa A. Bogusla...; Matthew C. Stout; Zachary B. Madaj; Benjamin P. Caiello; Monica Pomaville; Elizabeth R. Wilson; Seneca S. Kinn-Gurzo; Curtis C. Parker; Sridhar M. Veluvolu; Taylor V. Brysgel; Rebecca Kaufman; Susan M. Kitchen-...; Jenna M. Gedminas; Patrick J. Grohar
• Keywords: FLI1

<div>AbstractPurpose:<p>The importance of cellular context to the synergy DNA damage response (DDR)-targeted agents is important for tumors with mutations in DDR pathways, but less well-established driven by oncogenic transcription factors. In this study, we exploit widespread transcriptional dysregulation EWS-FLI1 factor identify an effective DDR-targeted combination therapy Ewing sarcoma.</p>Experimental Design:<p>We used matrix drug screening evaluate between a DNA-PK inhibitor (M9831) or ATR (berzosertib) and chemotherapy. The berzosertib cisplatin was selected broad synergy, mechanistically evaluated sarcoma selectivity, optimized <i>in vivo</i> schedule.</p>Results:<p>Berzosertib combined demonstrates profound multiple cell lines at clinically achievable concentrations. due loss expression downstream target CHEK1, cell-cycle check-points, mitotic catastrophe. Consistent goals project, drives CHEK1 five other pathway members. not repression instead caused degradation coupled suppression protein translation. realized novel schedule subsets models, leading durable complete responses 50% animals bearing two different xenografts.</p>Conclusions:<p>These data alterations broaden therapeutic window establish promising schedule.</p><p><i><a href="https://aacrjournals.org/clincancerres/article-abstract/doi/10.1158/1078-0432.CCR-24-1047" target="_blank">See related commentary Ohmura Grünewald, p. 3358</a></i></p></div>