ATR Is a Therapeutic Target in Synovial Sarcoma.
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Authors
Jones, SE
Fleuren, EDG
Frankum, J
Konde, A
Williamson, CT
Krastev, DB
Pemberton, HN
Campbell, J
Gulati, A
Elliott, R
Menon, M
Selfe, JL
Brough, R
Pettitt, SJ
Niedzwiedz, W
van der Graaf, WTA
Shipley, J
Ashworth, A
Lord, CJ
Fleuren, EDG
Frankum, J
Konde, A
Williamson, CT
Krastev, DB
Pemberton, HN
Campbell, J
Gulati, A
Elliott, R
Menon, M
Selfe, JL
Brough, R
Pettitt, SJ
Niedzwiedz, W
van der Graaf, WTA
Shipley, J
Ashworth, A
Lord, CJ
Document Type
Journal Article
Date
2017-12-15
Date Accepted
2017-10-10
Abstract
Synovial sarcoma (SS) is an aggressive soft-tissue malignancy characterized by expression of SS18-SSX fusions, where treatment options are limited. To identify therapeutically actionable genetic dependencies in SS, we performed a series of parallel, high-throughput small interfering RNA (siRNA) screens and compared genetic dependencies in SS tumor cells with those in >130 non-SS tumor cell lines. This approach revealed a reliance of SS tumor cells upon the DNA damage response serine/threonine protein kinase ATR. Clinical ATR inhibitors (ATRi) elicited a synthetic lethal effect in SS tumor cells and impaired growth of SS patient-derived xenografts. Oncogenic SS18-SSX family fusion genes are known to alter the composition of the BAF chromatin-remodeling complex, causing ejection and degradation of wild-type SS18 and the tumor suppressor SMARCB1. Expression of oncogenic SS18-SSX fusion proteins caused profound ATRi sensitivity and a reduction in SS18 and SMARCB1 protein levels, but an SSX18-SSX1 Δ71-78 fusion containing a C-terminal deletion did not. ATRi sensitivity in SS was characterized by an increase in biomarkers of replication fork stress (increased γH2AX, decreased replication fork speed, and increased R-loops), an apoptotic response, and a dependence upon cyclin E expression. Combinations of cisplatin or PARP inhibitors enhanced the antitumor cell effect of ATRi, suggesting that either single-agent ATRi or combination therapy involving ATRi might be further assessed as candidate approaches for SS treatment. Cancer Res; 77(24); 7014-26. ©2017 AACR.
Citation
Cancer research, 2017, 77 (24), pp. 7014 - 7026
Source Title
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
0008-5472
eISSN
1538-7445
Research Team
Cancer and Genome Instability
Clinical and Translational Sarcoma
Gene Function
Sarcoma Molecular Pathology
Clinical and Translational Sarcoma
Gene Function
Sarcoma Molecular Pathology