Therapeutic targeting of ATR in alveolar rhabdomyosarcoma

Heathcliff Dorado García, Fabian Pusch, Yi Bei, Jennifer Stebut, Glorymar Ibáñez, Kristina Guillan, Koshi Imami, Dennis Gürgen, Jana Rolff, Konstantin Helmsauer, Stephanie Meyer-Liesener, Natalie Timme, Victor Bardinet, Rocío Chamorro González, Ian C. MacArthur, Celine Y. Chen, Joachim Schulz, Antje M. Wengner, Christian Furth, Birgit Lala, Angelika Eggert, Georg Seifert, Patrick Hundsoerfer, Marieluise Kirchner, Philipp Mertins, Matthias Selbach, Andrej Lissat, Frank Dubois, David Horst, Johannes H. Schulte, Simone Spuler, Daoqi You, Filemon Cruz, Andrew L. Kung, Kerstin Haase, Michela DiVirgilio, Monika Scheer, Michael V. Ortiz and Anton G. Henssen ()
Additional contact information
Heathcliff Dorado García: Experimental and Clinical Research Center (ECRC) of the MDC and Charité Berlin
Fabian Pusch: Experimental and Clinical Research Center (ECRC) of the MDC and Charité Berlin
Yi Bei: Experimental and Clinical Research Center (ECRC) of the MDC and Charité Berlin
Jennifer Stebut: Experimental and Clinical Research Center (ECRC) of the MDC and Charité Berlin
Glorymar Ibáñez: Memorial Sloan Kettering Cancer Center
Kristina Guillan: Memorial Sloan Kettering Cancer Center
Koshi Imami: Max Delbrück Center for Molecular Medicine
Dennis Gürgen: Experimental Pharmacology and Oncology (EPO)
Jana Rolff: Experimental Pharmacology and Oncology (EPO)
Konstantin Helmsauer: Experimental and Clinical Research Center (ECRC) of the MDC and Charité Berlin
Stephanie Meyer-Liesener: Experimental and Clinical Research Center (ECRC) of the MDC and Charité Berlin
Natalie Timme: Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
Victor Bardinet: Experimental and Clinical Research Center (ECRC) of the MDC and Charité Berlin
Rocío Chamorro González: Experimental and Clinical Research Center (ECRC) of the MDC and Charité Berlin
Ian C. MacArthur: Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
Celine Y. Chen: Experimental and Clinical Research Center (ECRC) of the MDC and Charité Berlin
Joachim Schulz: Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
Antje M. Wengner: Bayer AG
Christian Furth: Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
Birgit Lala: Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
Angelika Eggert: Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
Georg Seifert: Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
Patrick Hundsoerfer: Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
Marieluise Kirchner: Max Delbrück Center for Molecular Medicine
Philipp Mertins: Max Delbrück Center for Molecular Medicine
Matthias Selbach: Max Delbrück Center for Molecular Medicine
Andrej Lissat: Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
Frank Dubois: Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
David Horst: Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
Johannes H. Schulte: Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
Simone Spuler: Experimental and Clinical Research Center (ECRC) of the MDC and Charité Berlin
Daoqi You: Memorial Sloan Kettering Cancer Center
Filemon Cruz: Memorial Sloan Kettering Cancer Center
Andrew L. Kung: Memorial Sloan Kettering Cancer Center
Kerstin Haase: Experimental and Clinical Research Center (ECRC) of the MDC and Charité Berlin
Michela DiVirgilio: Max Delbrück Center for Molecular Medicine
Monika Scheer: Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
Michael V. Ortiz: Memorial Sloan Kettering Cancer Center
Anton G. Henssen: Experimental and Clinical Research Center (ECRC) of the MDC and Charité Berlin

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-32023-7

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