American Association for Cancer Research
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Supplemental Table S7 from High-throughput Chemical Screening Identifies Focal Adhesion Kinase and Aurora Kinase B Inhibition as a Synergistic Treatment Combination in Ewing Sarcoma

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posted on 2023-03-31, 19:45 authored by Sarah Wang, Elizabeth E. Hwang, Rajarshi Guha, Allison F. O'Neill, Nicole Melong, Chansey J. Veinotte, Amy Conway Saur, Kellsey Wuerthele, Min Shen, Crystal McKnight, Gabriela Alexe, Madeleine E. Lemieux, Amy Wang, Emma Hughes, Xin Xu, Matthew B. Boxer, Matthew D. Hall, Andrew Kung, Jason N. Berman, Mindy I. Davis, Kimberly Stegmaier, Brian D. Crompton

Supplemental Table S7. Reverse Phase Protein Array (RPPA) data. Total protein and phosphorylation levels in untreated and treated A673 and TC32 cells are normalized to total protein levels in each sample.



Pediatric Cancer Research Foundation

Brian MacIsaac Sarcoma Foundation



Ewing sarcoma is an aggressive solid tumor malignancy of childhood. Although current treatment regimens cure approximately 70% of patients with localized disease, they are ineffective for most patients with metastases or relapse. New treatment combinations are necessary for these patients. Ewing sarcoma cells are dependent on focal adhesion kinase (FAK) for growth. To identify candidate treatment combinations for Ewing sarcoma, we performed a small-molecule library screen to identify compounds synergistic with FAK inhibitors in impairing Ewing cell growth. The activity of a top-scoring class of compounds was then validated across multiple Ewing cell lines in vitro and in multiple xenograft models of Ewing sarcoma. Numerous Aurora kinase inhibitors scored as synergistic with FAK inhibition in this screen. We found that Aurora kinase B inhibitors were synergistic across a larger range of concentrations than Aurora kinase A inhibitors when combined with FAK inhibitors in multiple Ewing cell lines. The combination of AZD-1152, an Aurora kinase B–selective inhibitor, and PF-562271 or VS-4718, FAK-selective inhibitors, induced apoptosis in Ewing sarcoma cells at concentrations that had minimal effects on survival when cells were treated with either drug alone. We also found that the combination significantly impaired tumor progression in multiple xenograft models of Ewing sarcoma. FAK and Aurora kinase B inhibitors synergistically impair Ewing sarcoma cell viability and significantly inhibit tumor progression. This study provides preclinical support for the consideration of a clinical trial testing the safety and efficacy of this combination for patients with Ewing sarcoma.

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