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An integrated chemical biology approach identifies specific vulnerability of Ewing's sarcoma to combined inhibition of Aurora kinases A and B.
- Source :
-
Molecular cancer therapeutics [Mol Cancer Ther] 2011 Oct; Vol. 10 (10), pp. 1846-56. Date of Electronic Publication: 2011 Jul 18. - Publication Year :
- 2011
-
Abstract
- Ewing's sarcoma is a pediatric cancer of the bone that is characterized by the expression of the chimeric transcription factor EWS-FLI1 that confers a highly malignant phenotype and results from the chromosomal translocation t(11;22)(q24;q12). Poor overall survival and pronounced long-term side effects associated with traditional chemotherapy necessitate the development of novel, targeted, therapeutic strategies. We therefore conducted a focused viability screen with 200 small molecule kinase inhibitors in 2 different Ewing's sarcoma cell lines. This resulted in the identification of several potential molecular intervention points. Most notably, tozasertib (VX-680, MK-0457) displayed unique nanomolar efficacy, which extended to other cell lines, but was specific for Ewing's sarcoma. Furthermore, tozasertib showed strong synergies with the chemotherapeutic drugs etoposide and doxorubicin, the current standard agents for Ewing's sarcoma. To identify the relevant targets underlying the specific vulnerability toward tozasertib, we determined its cellular target profile by chemical proteomics. We identified 20 known and unknown serine/threonine and tyrosine protein kinase targets. Additional target deconvolution and functional validation by RNAi showed simultaneous inhibition of Aurora kinases A and B to be responsible for the observed tozasertib sensitivity, thereby revealing a new mechanism for targeting Ewing's sarcoma. We further corroborated our cellular observations with xenograft mouse models. In summary, the multilayered chemical biology approach presented here identified a specific vulnerability of Ewing's sarcoma to concomitant inhibition of Aurora kinases A and B by tozasertib and danusertib, which has the potential to become a new therapeutic option.
- Subjects :
- Animals
Apoptosis drug effects
Aurora Kinases
Bone Neoplasms enzymology
Bone Neoplasms genetics
Bone Neoplasms pathology
Cell Cycle drug effects
Down-Regulation drug effects
Drug Synergism
Gene Knockdown Techniques
Humans
Mice
Mice, SCID
Oncogene Proteins, Fusion biosynthesis
Oncogene Proteins, Fusion genetics
Piperazines pharmacology
Protein Serine-Threonine Kinases genetics
Proto-Oncogene Protein c-fli-1 biosynthesis
Proto-Oncogene Protein c-fli-1 genetics
RNA Interference
RNA-Binding Protein EWS biosynthesis
RNA-Binding Protein EWS genetics
Random Allocation
Sarcoma, Ewing enzymology
Sarcoma, Ewing genetics
Sarcoma, Ewing pathology
Xenograft Model Antitumor Assays
Bone Neoplasms drug therapy
Protein Kinase Inhibitors pharmacology
Protein Serine-Threonine Kinases antagonists & inhibitors
Sarcoma, Ewing drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1538-8514
- Volume :
- 10
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Molecular cancer therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 21768330
- Full Text :
- https://doi.org/10.1158/1535-7163.MCT-11-0100