Combinations of PARP Inhibitors with Temozolomide Drive PARP1 Trapping and Apoptosis in Ewing's Sarcoma.
Ewing's sarcoma is a malignant pediatric bone tumor with a poor prognosis for patients with metastatic or recurrent disease. Ewing's sarcoma cells are acutely hypersensitive to poly (ADP-ribose) polymerase (PARP) inhibition and this is being evaluated in clinical trials, although the mechanism of hypersensitivity has not been directly addressed. PARP inhibitors have efficacy in tumors with BRCA1/2 mutations, which confer deficiency in DNA double-strand break (DSB) repair by homologous recombination (HR). This drives dependence on PARP1/2 due to their function in DNA single-strand break (SSB) repair. PARP inhibitors are also cytotoxic through inhibiting PARP1/2 auto-PARylation, blocking PARP1/2 release from substrate DNA. Here, we show that PARP inhibitor sensitivity in Ewing's sarcoma cells is not through an apparent defect in DNA repair by HR, but through hypersensitivity to trapped PARP1-DNA complexes. This drives accumulation of DNA damage during replication, ultimately leading to apoptosis. We also show that the activity of PARP inhibitors is potentiated by temozolomide in Ewing's sarcoma cells and is associated with enhanced trapping of PARP1-DNA complexes. Furthermore, through mining of large-scale drug sensitivity datasets, we identify a subset of glioma, neuroblastoma and melanoma cell lines as hypersensitive to the combination of temozolomide and PARP inhibition, potentially identifying new avenues for therapeutic intervention. These data provide insights into the anti-cancer activity of PARP inhibitors with implications for the design of treatment for Ewing's sarcoma patients with PARP inhibitors.
Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
Sonja J
SJ
Gill
The Wellcome Trust/Cancer Research UK Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
Jon
J
Travers
Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
Irina
I
Pshenichnaya
Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
Fiona A
FA
Kogera
Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
Syd
S
Barthorpe
Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
Tatiana
T
Mironenko
Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
Laura
L
Richardson
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts, United States of America.
Cyril H
CH
Benes
Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
Michael R
MR
Stratton
Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
Ultan
U
McDermott
Wellcome Trust Sanger Institute, Hinxton, United Kingdom; The Wellcome Trust/Cancer Research UK Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
Stephen P
SP
Jackson
Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
Mathew J
MJ
Garnett
D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D053904:DNA Breaks, Single-Stranded / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D059765:Homologous Recombination / Q000235:genetics; D006801:Humans; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage*; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis*; D012512:Sarcoma, Ewing / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000077204:Temozolomide
D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D003606:Dacarbazine; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D000077204:Temozolomide