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author Dorado García, Heathcliff
Pusch, Fabian
Bei, Yi
von Stebut, Jennifer
Ibáñez, Glorymar
Guillan, Kristina
Imami, Koshi
Gürgen, Dennis
Rolff, Jana
Helmsauer, Konstantin
Meyer-Liesener, Stephanie
Timme, Natalie
Bardinet, Victor
Chamorro González, Rocío
MacArthur, Ian C.
Chen, Celine Y.
Schulz, Joachim
Wengner, Antje M.
Furth, Christian
Lala, Birgit
Eggert, Angelika
Seifert, Georg
Hundsoerfer, Patrick
Kirchner, Marieluise
Mertins, Philipp
Selbach, Matthias
Lissat, Andrej
Dubois, Frank
Horst, David
Schulte, Johannes H.
Spuler, Simone
You, Daoqi
Dela Cruz, Filemon
Kung, Andrew L.
Haase, Kerstin
DiVirgilio, Michela
Scheer, Monika
Ortiz, Michael V.
Henssen, Anton G.
author_facet Dorado García, Heathcliff
Pusch, Fabian
Bei, Yi
von Stebut, Jennifer
Ibáñez, Glorymar
Guillan, Kristina
Imami, Koshi
Gürgen, Dennis
Rolff, Jana
Helmsauer, Konstantin
Meyer-Liesener, Stephanie
Timme, Natalie
Bardinet, Victor
Chamorro González, Rocío
MacArthur, Ian C.
Chen, Celine Y.
Schulz, Joachim
Wengner, Antje M.
Furth, Christian
Lala, Birgit
Eggert, Angelika
Seifert, Georg
Hundsoerfer, Patrick
Kirchner, Marieluise
Mertins, Philipp
Selbach, Matthias
Lissat, Andrej
Dubois, Frank
Horst, David
Schulte, Johannes H.
Spuler, Simone
You, Daoqi
Dela Cruz, Filemon
Kung, Andrew L.
Haase, Kerstin
DiVirgilio, Michela
Scheer, Monika
Ortiz, Michael V.
Henssen, Anton G.
author_sort Dorado García, Heathcliff
collection PubMed
description Despite advances in multi-modal treatment approaches, clinical outcomes of patients suffering from PAX3-FOXO1 fusion oncogene-expressing alveolar rhabdomyosarcoma (ARMS) remain dismal. Here we show that PAX3-FOXO1-expressing ARMS cells are sensitive to pharmacological ataxia telangiectasia and Rad3 related protein (ATR) inhibition. Expression of PAX3-FOXO1 in muscle progenitor cells is not only sufficient to increase sensitivity to ATR inhibition, but PAX3-FOXO1-expressing rhabdomyosarcoma cells also exhibit increased sensitivity to structurally diverse inhibitors of ATR. Mechanistically, ATR inhibition leads to replication stress exacerbation, decreased BRCA1 phosphorylation and reduced homologous recombination-mediated DNA repair pathway activity. Consequently, ATR inhibitor treatment increases sensitivity of ARMS cells to PARP1 inhibition in vitro, and combined treatment with ATR and PARP1 inhibitors induces complete regression of primary patient-derived ARMS xenografts in vivo. Lastly, a genome-wide CRISPR activation screen (CRISPRa) in combination with transcriptional analyses of ATR inhibitor resistant ARMS cells identifies the RAS-MAPK pathway and its targets, the FOS gene family, as inducers of resistance to ATR inhibition. Our findings provide a rationale for upcoming biomarker-driven clinical trials of ATR inhibitors in patients suffering from ARMS.
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spelling pubmed-93143822022-07-27 Therapeutic targeting of ATR in alveolar rhabdomyosarcoma Dorado García, Heathcliff Pusch, Fabian Bei, Yi von Stebut, Jennifer Ibáñez, Glorymar Guillan, Kristina Imami, Koshi Gürgen, Dennis Rolff, Jana Helmsauer, Konstantin Meyer-Liesener, Stephanie Timme, Natalie Bardinet, Victor Chamorro González, Rocío MacArthur, Ian C. Chen, Celine Y. Schulz, Joachim Wengner, Antje M. Furth, Christian Lala, Birgit Eggert, Angelika Seifert, Georg Hundsoerfer, Patrick Kirchner, Marieluise Mertins, Philipp Selbach, Matthias Lissat, Andrej Dubois, Frank Horst, David Schulte, Johannes H. Spuler, Simone You, Daoqi Dela Cruz, Filemon Kung, Andrew L. Haase, Kerstin DiVirgilio, Michela Scheer, Monika Ortiz, Michael V. Henssen, Anton G. Nat Commun Article Despite advances in multi-modal treatment approaches, clinical outcomes of patients suffering from PAX3-FOXO1 fusion oncogene-expressing alveolar rhabdomyosarcoma (ARMS) remain dismal. Here we show that PAX3-FOXO1-expressing ARMS cells are sensitive to pharmacological ataxia telangiectasia and Rad3 related protein (ATR) inhibition. Expression of PAX3-FOXO1 in muscle progenitor cells is not only sufficient to increase sensitivity to ATR inhibition, but PAX3-FOXO1-expressing rhabdomyosarcoma cells also exhibit increased sensitivity to structurally diverse inhibitors of ATR. Mechanistically, ATR inhibition leads to replication stress exacerbation, decreased BRCA1 phosphorylation and reduced homologous recombination-mediated DNA repair pathway activity. Consequently, ATR inhibitor treatment increases sensitivity of ARMS cells to PARP1 inhibition in vitro, and combined treatment with ATR and PARP1 inhibitors induces complete regression of primary patient-derived ARMS xenografts in vivo. Lastly, a genome-wide CRISPR activation screen (CRISPRa) in combination with transcriptional analyses of ATR inhibitor resistant ARMS cells identifies the RAS-MAPK pathway and its targets, the FOS gene family, as inducers of resistance to ATR inhibition. Our findings provide a rationale for upcoming biomarker-driven clinical trials of ATR inhibitors in patients suffering from ARMS. Nature Publishing Group UK 2022-07-25 /pmc/articles/PMC9314382/ /pubmed/35879366 http://dx.doi.org/10.1038/s41467-022-32023-7 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Dorado García, Heathcliff
Pusch, Fabian
Bei, Yi
von Stebut, Jennifer
Ibáñez, Glorymar
Guillan, Kristina
Imami, Koshi
Gürgen, Dennis
Rolff, Jana
Helmsauer, Konstantin
Meyer-Liesener, Stephanie
Timme, Natalie
Bardinet, Victor
Chamorro González, Rocío
MacArthur, Ian C.
Chen, Celine Y.
Schulz, Joachim
Wengner, Antje M.
Furth, Christian
Lala, Birgit
Eggert, Angelika
Seifert, Georg
Hundsoerfer, Patrick
Kirchner, Marieluise
Mertins, Philipp
Selbach, Matthias
Lissat, Andrej
Dubois, Frank
Horst, David
Schulte, Johannes H.
Spuler, Simone
You, Daoqi
Dela Cruz, Filemon
Kung, Andrew L.
Haase, Kerstin
DiVirgilio, Michela
Scheer, Monika
Ortiz, Michael V.
Henssen, Anton G.
Therapeutic targeting of ATR in alveolar rhabdomyosarcoma
title Therapeutic targeting of ATR in alveolar rhabdomyosarcoma
title_full Therapeutic targeting of ATR in alveolar rhabdomyosarcoma
title_fullStr Therapeutic targeting of ATR in alveolar rhabdomyosarcoma
title_full_unstemmed Therapeutic targeting of ATR in alveolar rhabdomyosarcoma
title_short Therapeutic targeting of ATR in alveolar rhabdomyosarcoma
title_sort therapeutic targeting of atr in alveolar rhabdomyosarcoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9314382/
https://www.ncbi.nlm.nih.gov/pubmed/35879366
http://dx.doi.org/10.1038/s41467-022-32023-7
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