PDE3A-SLFN12 Molecular Glues Target Multiple KIT D816V Cell Types in Preclinical Models of Mast Cell Malignancies
bioRxiv (Cold Spring Harbor Laboratory)
Abstract
Abstract A drug discovery approach was used to specifically target malignant cells with KIT D816V mutation, which is the predominant disease-causing mutation in clonal mast cell malignancies. To this end, KIT D816V cells derived from induced pluripotent stem cells (iPS cells) of KIT D816V patients were employed to screen a library of FDA approved and experimental drugs for specific killing of KIT D816V cells. We discovered the novel compound LDC 3416, which targets multiple malignant KIT D816V cell types, including hematopoietic stem/progenitor cells and mast cells. Importantly, by exploring the LDC 3416 targeting profile, we identified the phosphodiesterase 3A- Schlafen 12 (PDE3A-SLFN12) molecular glue pathway as a novel approach for specific targeting of malignant KIT D816V cells. We found that the KIT D816V mutant protein leads to increased expression of PDE3A and SLFN12 and thus confers a selective molecular vulnerability to PDE3A-SLFN12 molecular glues. Primary malignant mast cells of KIT D816V patients with indolent and advanced systemic mastocytosis also exhibit increased expression of PDE3A and SLFN12. We extended our study to include additional PDE3A-SLFN12 molecular glues and demonstrate their synergistic action with KIT D816V selective tyrosine kinase inhibitors (TKIs) in killing KIT D816V cells. Furthermore, the PDE3A-SLFN12 molecular glues also target KIT D816V megakaryocytes, a cell type that has been underestimated in malignant mast cell pathophysiology and molecular targeting. The identified molecular glues, along with their synergy with TKIs and their simultaneous targeting of multiple KIT D816V cell types, open novel treatment options for KIT D816V mast cell malignancies and other KIT D816V associated diseases.
Authors 23
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Affiliation as printed
Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), 52074 Aachen, Germany
Department of Medicine IV, Haematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany
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Affiliation as printed
Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), 52074 Aachen, Germany
Department of Medicine IV, Haematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany
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Affiliation as printed
Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), 52074 Aachen, Germany
Department of Medicine IV, Haematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany
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Lead Discovery Center (Germany)
Affiliation as printed
Lead Discovery Center, LDC, 44227 Dortmund, Germany
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Lead Discovery Center (Germany)
Affiliation as printed
Lead Discovery Center, LDC, 44227 Dortmund, Germany
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Affiliation as printed
Institute for Computational Genomics, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany
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Forschungszentrum Jülich · Universitätsklinikum Aachen · Jülich Supercomputing Centre · RWTH Aachen University
Affiliation as printed
Computational Biomedicine, Institute of Neuroscience and Medicine, INM-9, Forschungszentrum Juelich, 52425 Juelich, Germany
Department of Neurology, RWTH Aachen University Hospital, 52074 Aachen, Germany
Juelich Supercomputing Center, JSC, Forschungszentrum Juelich, 52425 Juelich, Germany
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Affiliation as printed
Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), 52074 Aachen, Germany
Department of Medicine IV, Haematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany
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Affiliation as printed
Institute of Cell and Tumor Biology, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany
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Affiliation as printed
Institute of Cell and Tumor Biology, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany
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Affiliation as printed
Institute of Pathology, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany
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Affiliation as printed
Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), 52074 Aachen, Germany
Department of Medicine IV, Haematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany
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Affiliation as printed
Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), 52074 Aachen, Germany
Department of Medicine IV, Haematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany
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Affiliation as printed
Department of Developmental Biology, Medical Faculty, Institute of Pathology, University of Bonn, 53127 Bonn, Germany
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Pitié-Salpêtrière Hospital · Paris-Sorbonne University
Affiliation as printed
CEREMAST, Department of Hematological Biology, Pitié-Salpêtrière Hospital, Paris Sorbonne University, Paris, France
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Broad Institute · Harvard University
Affiliation as printed
Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
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Forschungszentrum Jülich · Universitätsklinikum Aachen · Jülich Supercomputing Centre · RWTH Aachen University
Affiliation as printed
Computational Biomedicine, Institute of Neuroscience and Medicine, INM-9, Forschungszentrum Juelich, 52425 Juelich, Germany
Department of Neurology, RWTH Aachen University Hospital, 52074 Aachen, Germany
Juelich Supercomputing Center, JSC, Forschungszentrum Juelich, 52425 Juelich, Germany
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Affiliation as printed
Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), 52074 Aachen, Germany
Department of Medicine IV, Haematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany
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Affiliation as printed
Institute for Computational Genomics, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany
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Affiliation as printed
Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), 52074 Aachen, Germany
Department of Medicine IV, Haematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany
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Affiliation as printed
Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), 52074 Aachen, Germany
Department of Medicine IV, Haematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany
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Lead Discovery Center (Germany)
Affiliation as printed
Lead Discovery Center, LDC, 44227 Dortmund, Germany
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Affiliation as printed
Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), 52074 Aachen, Germany
Department of Medicine IV, Haematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany
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