Therapeutic targeting of ATR in alveolar rhabdomyosarcoma
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Published:2022-07-25
Issue:1
Volume:13
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Dorado García HeathcliffORCID, Pusch FabianORCID, Bei YiORCID, von Stebut JenniferORCID, Ibáñez Glorymar, Guillan Kristina, Imami KoshiORCID, Gürgen Dennis, Rolff Jana, Helmsauer KonstantinORCID, Meyer-Liesener Stephanie, Timme Natalie, Bardinet Victor, Chamorro González Rocío, MacArthur Ian C.ORCID, Chen Celine Y., Schulz Joachim, Wengner Antje M., Furth Christian, Lala Birgit, Eggert AngelikaORCID, Seifert Georg, Hundsoerfer Patrick, Kirchner MarieluiseORCID, Mertins PhilippORCID, Selbach MatthiasORCID, Lissat Andrej, Dubois Frank, Horst David, Schulte Johannes H.ORCID, Spuler SimoneORCID, You Daoqi, Dela Cruz Filemon, Kung Andrew L.ORCID, Haase KerstinORCID, DiVirgilio MichelaORCID, Scheer Monika, Ortiz Michael V., Henssen Anton G.ORCID
Abstract
AbstractDespite 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.
Funder
Deutsche Forschungsgemeinschaft Deutsche Krebshilfe EC | Horizon 2020 Framework Programme "la Caixa" Foundation
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference86 articles.
1. Ognjanovic, S., Linabery, A. M., Charbonneau, B. & Ross, J. A. Trends in childhood rhabdomyosarcoma incidence and survival in the United States, 1975–2005. Cancer 115, 4218–4226 (2009). 2. Douglass, E. C. et al. A specific chromosomal abnormality in rhabdomyosarcoma. Cytogenet Cell Genet. 45, 148–155 (1987). 3. Douglass, E. C. et al. Variant translocations of chromosome 13 in alveolar rhabdomyosarcoma. Genes Chromosomes Cancer 3, 480–482 (1991). 4. Keller, C. et al. Alveolar rhabdomyosarcomas in conditional Pax3:Fkhr mice: Cooperativity of Ink4a/ARF and Trp53 loss of function. Genes Dev. 18, 2614–2626 (2004). 5. Perkins, S. M., Shinohara, E. T., DeWees, T. & Frangoul, H. Outcome for children with metastatic solid tumors over the last four decades. PLoS One 9, e100396 (2014).
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