ATR Is a Therapeutic Target in Synovial Sarcoma.
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Date
2017-12-15ICR Author
Author
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
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Tumor Cells, Cultured
Animals
Mice, Inbred BALB C
Mice, Inbred NOD
Humans
Mice
Mice, Nude
Mice, SCID
Sarcoma, Synovial
Recombinant Fusion Proteins
RNA, Small Interfering
Antineoplastic Agents
Xenograft Model Antitumor Assays
Cell Death
Cell Proliferation
RNA Interference
Female
Molecular Targeted Therapy
Ataxia Telangiectasia Mutated Proteins
Research team
Cancer and Genome Instability
Clinical and Translational Sarcoma
Gene Function
Sarcoma Molecular Pathology
Language
eng
Date accepted
2017-10-10
License start date
2017-12
Citation
Cancer research, 2017, 77 (24), pp. 7014 - 7026
Publisher
AMER ASSOC CANCER RESEARCH