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Resistance to PARP inhibitors by SLFN11 inactivation can be overcome by ATR inhibition
Poly(ADP-ribose) polymerase inhibitors (PARPIs) kill cancer cells by trapping PARP1 and PARP2. Talazoparib, the most potent PARPI inhibitor (PARPI), exhibits remarkable selectivity among the NCI-60 cancer cell lines beyond BRCA inactivation. Our genomic analyses reveal high correlation between respo...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5340226/ https://www.ncbi.nlm.nih.gov/pubmed/27708213 http://dx.doi.org/10.18632/oncotarget.12266 |
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author | Murai, Junko Feng, Ying Yu, Guoying K. Ru, Yuanbin Tang, Sai-Wen Shen, Yuqiao Pommier, Yves |
author_facet | Murai, Junko Feng, Ying Yu, Guoying K. Ru, Yuanbin Tang, Sai-Wen Shen, Yuqiao Pommier, Yves |
author_sort | Murai, Junko |
collection | PubMed |
description | Poly(ADP-ribose) polymerase inhibitors (PARPIs) kill cancer cells by trapping PARP1 and PARP2. Talazoparib, the most potent PARPI inhibitor (PARPI), exhibits remarkable selectivity among the NCI-60 cancer cell lines beyond BRCA inactivation. Our genomic analyses reveal high correlation between response to talazoparib and Schlafen 11 (SLFN11) expression. Causality was established in four isogenic SLFN11-positive and -negative cell lines and extended to olaparib. Response to the talazoparib-temozolomide combination was also driven by SLFN11 and validated in 36 small cell lung cancer cell lines, and in xenograft models. Resistance in SLFN11-deficient cells was caused neither by impaired drug penetration nor by activation of homologous recombination. Rather, SLFN11 induced irreversible and lethal replication inhibition, which was independent of ATR-mediated S-phase checkpoint. The resistance to PARPIs by SLFN11 inactivation was overcome by ATR inhibition, mechanistically because SLFN11-deficient cells solely rely on ATR activation for their survival under PARPI treatment. Our study reveals that SLFN11 inactivation, which is common (~45%) in cancer cells, is a novel and dominant resistance determinant to PARPIs. |
format | Online Article Text |
id | pubmed-5340226 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-53402262017-03-08 Resistance to PARP inhibitors by SLFN11 inactivation can be overcome by ATR inhibition Murai, Junko Feng, Ying Yu, Guoying K. Ru, Yuanbin Tang, Sai-Wen Shen, Yuqiao Pommier, Yves Oncotarget Research Paper Poly(ADP-ribose) polymerase inhibitors (PARPIs) kill cancer cells by trapping PARP1 and PARP2. Talazoparib, the most potent PARPI inhibitor (PARPI), exhibits remarkable selectivity among the NCI-60 cancer cell lines beyond BRCA inactivation. Our genomic analyses reveal high correlation between response to talazoparib and Schlafen 11 (SLFN11) expression. Causality was established in four isogenic SLFN11-positive and -negative cell lines and extended to olaparib. Response to the talazoparib-temozolomide combination was also driven by SLFN11 and validated in 36 small cell lung cancer cell lines, and in xenograft models. Resistance in SLFN11-deficient cells was caused neither by impaired drug penetration nor by activation of homologous recombination. Rather, SLFN11 induced irreversible and lethal replication inhibition, which was independent of ATR-mediated S-phase checkpoint. The resistance to PARPIs by SLFN11 inactivation was overcome by ATR inhibition, mechanistically because SLFN11-deficient cells solely rely on ATR activation for their survival under PARPI treatment. Our study reveals that SLFN11 inactivation, which is common (~45%) in cancer cells, is a novel and dominant resistance determinant to PARPIs. Impact Journals LLC 2016-09-27 /pmc/articles/PMC5340226/ /pubmed/27708213 http://dx.doi.org/10.18632/oncotarget.12266 Text en Copyright: © 2016 Murai et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Murai, Junko Feng, Ying Yu, Guoying K. Ru, Yuanbin Tang, Sai-Wen Shen, Yuqiao Pommier, Yves Resistance to PARP inhibitors by SLFN11 inactivation can be overcome by ATR inhibition |
title | Resistance to PARP inhibitors by SLFN11 inactivation can be overcome by ATR inhibition |
title_full | Resistance to PARP inhibitors by SLFN11 inactivation can be overcome by ATR inhibition |
title_fullStr | Resistance to PARP inhibitors by SLFN11 inactivation can be overcome by ATR inhibition |
title_full_unstemmed | Resistance to PARP inhibitors by SLFN11 inactivation can be overcome by ATR inhibition |
title_short | Resistance to PARP inhibitors by SLFN11 inactivation can be overcome by ATR inhibition |
title_sort | resistance to parp inhibitors by slfn11 inactivation can be overcome by atr inhibition |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5340226/ https://www.ncbi.nlm.nih.gov/pubmed/27708213 http://dx.doi.org/10.18632/oncotarget.12266 |
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