ATR Is a Therapeutic Target in Synovial Sarcoma

Samuel E Jones, Emmy D G Fleuren, Jessica Frankum, Asha Konde, Chris T Williamson, Dragomir B Krastev, Helen N Pemberton, James Campbell, Aditi Gulati, Richard Elliott, Malini Menon, Joanna L Selfe, Rachel Brough, Stephen J Pettitt, Wojciech Niedzwiedz, Winette T A van der Graaf, Janet Shipley, Alan Ashworth, Christopher J Lord

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)7014-7026
Number of pages13
JournalCancer Research
Volume77
Issue number24
Early online date16 Oct 2017
DOIs
Publication statusPublished - 15 Dec 2017

Keywords

  • Animals
  • Antineoplastic Agents/administration & dosage
  • Ataxia Telangiectasia Mutated Proteins/antagonists & inhibitors
  • Cell Death/drug effects
  • Cell Proliferation/drug effects
  • Female
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred NOD
  • Mice, Nude
  • Mice, SCID
  • Molecular Targeted Therapy/methods
  • RNA Interference/physiology
  • RNA, Small Interfering/administration & dosage
  • Recombinant Fusion Proteins/administration & dosage
  • Sarcoma, Synovial/drug therapy
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

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