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Therapeutic targeting of ATR in alveolar rhabdomyosarcoma

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  • Heathcliff Dorado García

    (Experimental and Clinical Research Center (ECRC) of the MDC and Charité Berlin
    Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
    Max Delbrück Center for Molecular Medicine)

  • 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
    Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
    Max Delbrück Center for Molecular Medicine)

  • Jennifer Stebut

    (Experimental and Clinical Research Center (ECRC) of the MDC and Charité Berlin
    Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu 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
    Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin)

  • Stephanie Meyer-Liesener

    (Experimental and Clinical Research Center (ECRC) of the MDC and Charité Berlin
    Max Delbrück Center for Molecular Medicine
    Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Experimental and Clinical Research Center, Charité Campus Buch)

  • 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
    Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin)

  • Rocío Chamorro González

    (Experimental and Clinical Research Center (ECRC) of the MDC and Charité Berlin
    Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
    Max Delbrück Center for Molecular Medicine)

  • 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
    Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu 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
    Berlin Institute of Health)

  • Philipp Mertins

    (Max Delbrück Center for Molecular Medicine
    Berlin Institute of Health)

  • 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
    Berlin Institute of Health at Charité – Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Junior Clinician Scientist Program)

  • 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
    Max Delbrück Center for Molecular Medicine
    Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Experimental and Clinical Research Center, Charité Campus Buch
    Berlin Institute of Health)

  • 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
    Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
    Max Delbrück Center for Molecular Medicine
    Berlin Institute of Health)

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.

Suggested Citation

  • Heathcliff Dorado García & Fabian Pusch & Yi Bei & Jennifer Stebut & Glorymar Ibáñez & Kristina Guillan & Koshi Imami & Dennis Gürgen & Jana Rolff & Konstantin Helmsauer & Stephanie Meyer-Liesener & N, 2022. "Therapeutic targeting of ATR in alveolar rhabdomyosarcoma," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32023-7
    DOI: 10.1038/s41467-022-32023-7
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    References listed on IDEAS

    as
    1. Silvana Konermann & Mark D. Brigham & Alexandro E. Trevino & Julia Joung & Omar O. Abudayyeh & Clea Barcena & Patrick D. Hsu & Naomi Habib & Jonathan S. Gootenberg & Hiroshi Nishimasu & Osamu Nureki &, 2015. "Genome-scale transcriptional activation by an engineered CRISPR-Cas9 complex," Nature, Nature, vol. 517(7536), pages 583-588, January.
    2. Aparna Gorthi & July Carolina Romero & Eva Loranc & Lin Cao & Liesl A. Lawrence & Elicia Goodale & Amanda Balboni Iniguez & Xavier Bernard & V. Pragathi Masamsetti & Sydney Roston & Elizabeth R. Lawlo, 2018. "EWS–FLI1 increases transcription to cause R-loops and block BRCA1 repair in Ewing sarcoma," Nature, Nature, vol. 555(7696), pages 387-391, March.
    3. Cheng-Zhong Zhang & Alexander Spektor & Hauke Cornils & Joshua M. Francis & Emily K. Jackson & Shiwei Liu & Matthew Meyerson & David Pellman, 2015. "Chromothripsis from DNA damage in micronuclei," Nature, Nature, vol. 522(7555), pages 179-184, June.
    4. Neil Vasan & José Baselga & David M. Hyman, 2019. "A view on drug resistance in cancer," Nature, Nature, vol. 575(7782), pages 299-309, November.
    5. Hannah Farmer & Nuala McCabe & Christopher J. Lord & Andrew N. J. Tutt & Damian A. Johnson & Tobias B. Richardson & Manuela Santarosa & Krystyna J. Dillon & Ian Hickson & Charlotte Knights & Niall M. , 2005. "Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy," Nature, Nature, vol. 434(7035), pages 917-921, April.
    6. Adrian Vallejo & Naiara Perurena & Elisabet Guruceaga & Pawel K. Mazur & Susana Martinez-Canarias & Carolina Zandueta & Karmele Valencia & Andrea Arricibita & Dana Gwinn & Leanne C. Sayles & Chen-Hua , 2017. "An integrative approach unveils FOSL1 as an oncogene vulnerability in KRAS-driven lung and pancreatic cancer," Nature Communications, Nature, vol. 8(1), pages 1-14, April.
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