ATR is a therapeutic target in synovial sarcoma.
van der Graaf, WTA
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Synovial sarcoma (SS) is an aggressive soft-tissue malignancy characterised 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 to those in >130 non-SS tumour 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 a 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 anti-tumor 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.
The Institute of Cancer Research (Grant ID: Unspecified)
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Cancer and Genome Instability
Clinical and Translational Sarcoma
Sarcoma Molecular Pathology
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Cancer Res, 2017