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 mecha...
Main Authors: | , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2015-01-01
|
Series: | PLoS ONE |
Online Access: | https://doi.org/10.1371/journal.pone.0140988 |
id |
doaj-b92378ffd7914656b8896f03d69dd08c |
---|---|
record_format |
Article |
spelling |
doaj-b92378ffd7914656b8896f03d69dd08c2021-03-04T12:33:14ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-011010e014098810.1371/journal.pone.0140988Combinations of PARP Inhibitors with Temozolomide Drive PARP1 Trapping and Apoptosis in Ewing's Sarcoma.Sonja J GillJon TraversIrina PshenichnayaFiona A KogeraSyd BarthorpeTatiana MironenkoLaura RichardsonCyril H BenesMichael R StrattonUltan McDermottStephen P JacksonMathew J GarnettEwing'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.https://doi.org/10.1371/journal.pone.0140988 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sonja J Gill Jon Travers Irina Pshenichnaya Fiona A Kogera Syd Barthorpe Tatiana Mironenko Laura Richardson Cyril H Benes Michael R Stratton Ultan McDermott Stephen P Jackson Mathew J Garnett |
spellingShingle |
Sonja J Gill Jon Travers Irina Pshenichnaya Fiona A Kogera Syd Barthorpe Tatiana Mironenko Laura Richardson Cyril H Benes Michael R Stratton Ultan McDermott Stephen P Jackson Mathew J Garnett Combinations of PARP Inhibitors with Temozolomide Drive PARP1 Trapping and Apoptosis in Ewing's Sarcoma. PLoS ONE |
author_facet |
Sonja J Gill Jon Travers Irina Pshenichnaya Fiona A Kogera Syd Barthorpe Tatiana Mironenko Laura Richardson Cyril H Benes Michael R Stratton Ultan McDermott Stephen P Jackson Mathew J Garnett |
author_sort |
Sonja J Gill |
title |
Combinations of PARP Inhibitors with Temozolomide Drive PARP1 Trapping and Apoptosis in Ewing's Sarcoma. |
title_short |
Combinations of PARP Inhibitors with Temozolomide Drive PARP1 Trapping and Apoptosis in Ewing's Sarcoma. |
title_full |
Combinations of PARP Inhibitors with Temozolomide Drive PARP1 Trapping and Apoptosis in Ewing's Sarcoma. |
title_fullStr |
Combinations of PARP Inhibitors with Temozolomide Drive PARP1 Trapping and Apoptosis in Ewing's Sarcoma. |
title_full_unstemmed |
Combinations of PARP Inhibitors with Temozolomide Drive PARP1 Trapping and Apoptosis in Ewing's Sarcoma. |
title_sort |
combinations of parp inhibitors with temozolomide drive parp1 trapping and apoptosis in ewing's sarcoma. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2015-01-01 |
description |
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. |
url |
https://doi.org/10.1371/journal.pone.0140988 |
work_keys_str_mv |
AT sonjajgill combinationsofparpinhibitorswithtemozolomidedriveparp1trappingandapoptosisinewingssarcoma AT jontravers combinationsofparpinhibitorswithtemozolomidedriveparp1trappingandapoptosisinewingssarcoma AT irinapshenichnaya combinationsofparpinhibitorswithtemozolomidedriveparp1trappingandapoptosisinewingssarcoma AT fionaakogera combinationsofparpinhibitorswithtemozolomidedriveparp1trappingandapoptosisinewingssarcoma AT sydbarthorpe combinationsofparpinhibitorswithtemozolomidedriveparp1trappingandapoptosisinewingssarcoma AT tatianamironenko combinationsofparpinhibitorswithtemozolomidedriveparp1trappingandapoptosisinewingssarcoma AT laurarichardson combinationsofparpinhibitorswithtemozolomidedriveparp1trappingandapoptosisinewingssarcoma AT cyrilhbenes combinationsofparpinhibitorswithtemozolomidedriveparp1trappingandapoptosisinewingssarcoma AT michaelrstratton combinationsofparpinhibitorswithtemozolomidedriveparp1trappingandapoptosisinewingssarcoma AT ultanmcdermott combinationsofparpinhibitorswithtemozolomidedriveparp1trappingandapoptosisinewingssarcoma AT stephenpjackson combinationsofparpinhibitorswithtemozolomidedriveparp1trappingandapoptosisinewingssarcoma AT mathewjgarnett combinationsofparpinhibitorswithtemozolomidedriveparp1trappingandapoptosisinewingssarcoma |
_version_ |
1714802301868179456 |