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Clin Cancer Res DOI:10.1158/1078-0432.CCR-17-0375

High-throughput Chemical Screening Identifies Focal Adhesion Kinase and Aurora Kinase B Inhibition as a Synergistic Treatment Combination in Ewing Sarcoma.

Publication TypeJournal Article
Year of Publication2019
AuthorsWang, S, Hwang, EE, Guha, R, O'Neill, AF, Melong, N, Veinotte, CJ, Saur, AConway, Wuerthele, K, Shen, M, McKnight, C, Alexe, G, Lemieux, ME, Wang, A, Hughes, E, Xu, X, Boxer, MB, Hall, MD, Kung, A, Berman, JN, Davis, MI, Stegmaier, K, Crompton, BD
JournalClin Cancer Res
Volume25
Issue14
Pages4552-4566
Date Published2019 Jul 15
ISSN1078-0432
Abstract

PURPOSE: 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.

EXPERIMENTAL DESIGN: 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 and in multiple xenograft models of Ewing sarcoma.

RESULTS: 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.

CONCLUSIONS: 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.

DOI10.1158/1078-0432.CCR-17-0375
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/30979745?dopt=Abstract

Alternate JournalClin. Cancer Res.
PubMed ID30979745
PubMed Central IDPMC6634997
Grant ListK08 CA188073 / CA / NCI NIH HHS / United States
R01 CA204915 / CA / NCI NIH HHS / United States