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YES1 Is a Druggable Oncogenic Target in SCLC

  • Esther Redin
    Affiliations
    Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain

    Centro de Investigación Biomédica en Red de Oncología (CIBERONC), The Carlos III Health Institute (ISCIII), Madrid, Spain

    Instituto de Investigación Sanitaria de Navarra (IDISNA), Navarra, Spain

    Department of Pathology, Anatomy, and Physiology, School of Medicine, University of Navarra, Pamplona, Spain
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  • Eva M. Garrido-Martin
    Affiliations
    Centro de Investigación Biomédica en Red de Oncología (CIBERONC), The Carlos III Health Institute (ISCIII), Madrid, Spain

    Oncology Business Unit, Cell Biology, Research and Development, PharmaMar, Madrid, Spain

    Lung Cancer Clinical Research Unit, Hospital 12 de Octubre-Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
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  • Karmele Valencia
    Affiliations
    Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain

    Centro de Investigación Biomédica en Red de Oncología (CIBERONC), The Carlos III Health Institute (ISCIII), Madrid, Spain

    Instituto de Investigación Sanitaria de Navarra (IDISNA), Navarra, Spain
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  • Miriam Redrado
    Affiliations
    Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain

    Instituto de Investigación Sanitaria de Navarra (IDISNA), Navarra, Spain
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  • Jose Luis Solorzano
    Affiliations
    Lung Cancer Clinical Research Unit, Hospital 12 de Octubre-Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain

    Anatomic Pathology and Molecular Diagnostics, MD Anderson Cancer Center Madrid, Spain
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  • Rafael Carias
    Affiliations
    Anatomic Pathology Unit, Fundacion Jimenez Diaz, Madrid, Spain
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  • Mirari Echepare
    Affiliations
    Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain

    Instituto de Investigación Sanitaria de Navarra (IDISNA), Navarra, Spain

    Department of Pathology, Anatomy, and Physiology, School of Medicine, University of Navarra, Pamplona, Spain
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  • Francisco Exposito
    Affiliations
    Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain

    Centro de Investigación Biomédica en Red de Oncología (CIBERONC), The Carlos III Health Institute (ISCIII), Madrid, Spain

    Instituto de Investigación Sanitaria de Navarra (IDISNA), Navarra, Spain

    Department of Pathology, Anatomy, and Physiology, School of Medicine, University of Navarra, Pamplona, Spain
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  • Diego Serrano
    Affiliations
    Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain

    Instituto de Investigación Sanitaria de Navarra (IDISNA), Navarra, Spain

    Department of Pathology, Anatomy, and Physiology, School of Medicine, University of Navarra, Pamplona, Spain
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  • Irene Ferrer
    Affiliations
    Centro de Investigación Biomédica en Red de Oncología (CIBERONC), The Carlos III Health Institute (ISCIII), Madrid, Spain

    Lung Cancer Clinical Research Unit, Hospital 12 de Octubre-Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
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  • Angel Nunez-Buiza
    Affiliations
    Lung Cancer Clinical Research Unit, Hospital 12 de Octubre-Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
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  • Irati Garmendia
    Affiliations
    Inflammation, Complement and Cancer Group, Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale (Inserm), Paris, France
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  • Juana M. García-Pedrero
    Affiliations
    Centro de Investigación Biomédica en Red de Oncología (CIBERONC), The Carlos III Health Institute (ISCIII), Madrid, Spain

    Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Instituto Universitario de Oncología del Principado de Asturias, University of Oviedo, Oviedo, Spain
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  • Alfonso Gurpide
    Affiliations
    Department of Oncology, Clinica Universidad de Navarra, Pamplona, Spain
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  • Luis Paz-Ares
    Affiliations
    Centro de Investigación Biomédica en Red de Oncología (CIBERONC), The Carlos III Health Institute (ISCIII), Madrid, Spain

    Lung Cancer Clinical Research Unit, Hospital 12 de Octubre-Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
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  • Katerina Politi
    Affiliations
    Yale Cancer Center, New Haven, Connecticut

    Department of Pathology, Yale School of Medicine, New Haven, Connecticut

    Section of Medical Oncology, Department of Medicine, Yale School of Medicine, New Haven, Connecticut
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  • Luis M. Montuenga
    Correspondence
    Corresponding author. Address for correspondence: Luis M. Montuenga, PhD, Program in Solid Tumors, CIMA of the University of Navarra, Avenida Pío XII, 55, 31008 Pamplona, Spain.
    Affiliations
    Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain

    Centro de Investigación Biomédica en Red de Oncología (CIBERONC), The Carlos III Health Institute (ISCIII), Madrid, Spain

    Instituto de Investigación Sanitaria de Navarra (IDISNA), Navarra, Spain

    Department of Pathology, Anatomy, and Physiology, School of Medicine, University of Navarra, Pamplona, Spain
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  • Alfonso Calvo
    Affiliations
    Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain

    Centro de Investigación Biomédica en Red de Oncología (CIBERONC), The Carlos III Health Institute (ISCIII), Madrid, Spain

    Instituto de Investigación Sanitaria de Navarra (IDISNA), Navarra, Spain

    Department of Pathology, Anatomy, and Physiology, School of Medicine, University of Navarra, Pamplona, Spain
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Published:August 18, 2022DOI:https://doi.org/10.1016/j.jtho.2022.08.002

      Abstract

      Introduction

      SCLC is an extremely aggressive subtype of lung cancer without approved targeted therapies. Here we identified YES1 as a novel targetable oncogene driving SCLC maintenance and metastasis.

      Methods

      Association between YES1 levels and prognosis was evaluated in SCLC clinical samples. In vitro functional experiments for proliferation, apoptosis, cell cycle, and cytotoxicity were performed. Genetic and pharmacologic inhibition of YES1 was evaluated in vivo in cell- and patient-derived xenografts and metastasis. YES1 levels were evaluated in mouse and patient plasma-derived exosomes.

      Results

      Overexpression or gain/amplification of YES1 was identified in 31% and 26% of cases, respectively, across molecular subgroups, and was found as an independent predictor of poor prognosis. Genetic depletion of YES1 dramatically reduced cell proliferation, three-dimensional organoid formation, tumor growth, and distant metastasis, leading to extensive apoptosis and tumor regressions. Mechanistically, YES1-inhibited cells revealed alterations in the replisome and DNA repair processes, that conferred sensitivity to irradiation. Pharmacologic blockade with the novel YES1 inhibitor CH6953755 or dasatinib induced marked antitumor activity in organoid models and cell- and patient-derived xenografts. YES1 protein was detected in plasma exosomes from patients and mouse models, with levels matching those of tumors, suggesting that circulating YES1 could represent a biomarker for patient selection/monitoring.

      Conclusions

      Our results provide evidence that YES1 is a new druggable oncogenic target and biomarker to advance the clinical management of a subpopulation of patients with SCLC.

      Keywords

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