https://phaidra.vetmeduni.ac.at/o:1699 Blocking STAT3/5 through direct or upstream kinase targeting in leukemic cutaneous T-cell lymphoma Sorger, Helena Helena Sorger 0000-0002-3380-7770 University of Veterinary Medicine, Vienna / Medical University Vienna / University of Vienna Wolf, Peter Peter Wolf 0000-0001-7777-9444 Medical University of Graz Kenner, Lukas Lukas Kenner 0000-0003-0918-9463 University of Veterinary Medicine Vienna Gunning, Patrick T. Patrick T. Gunning 0000-0003-0654-735X University of Toronto Heitzer, Ellen Ellen Heitzer Medical University of Graz Herling, Marco Marco Herling Cologne University / University of Leipzig Merkel, Olaf Olaf Merkel Medical University of Vienna Fleck, Roman Roman Fleck Neubauer, Heidi A Heidi A Neubauer 0000-0001-7372-7786 University of Veterinary Medicine Vienna Nguyen, Van Anh Van Anh Nguyen 0000-0003-2087-447X Medical University of Innsbruck André, Fiona Fiona André Medical University of Innsbruck Nicolay, Jan P. Jan P. Nicolay University Hospital Mannheim Wobser, Marion Marion Wobser University Hospital Wuerzburg Berger, Walter Walter Berger Medical University of Vienna Orlova, Anna Anna Orlova 0000-0001-9262-7529 University of Veterinary Medicine Vienna Metzelder, Martin L. Martin L. Metzelder Medical University of Vienna Olaoye, Olasunkanmi O. Olasunkanmi O. Olaoye University of Toronto Manaswiyoungkul, Pimyupa Pimyupa Manaswiyoungkul University of Toronto Abdeldayem, Ayah Ayah Abdeldayem University of Toronto Tin, Gary Gary Tin University of Toronto Albrecht, Jana D Jana D Albrecht University Hospital Mannheim Otte, Moritz Moritz Otte Cologne University Ober, Jennifer Jennifer Ober Medical University of Graz Cerroni, Lorenzo Lorenzo Cerroni Medical University of Graz Fink-Puches, Regina Regina Fink-Puches Medical University of Graz Pan, Yi Yi Pan 0000-0001-6723-1370 Medical University of Graz Perchthaler, Isabella Isabella Perchthaler Medical University of Graz Graier, Thomas Thomas Graier Medical University of Graz Machtinger, Michael Michael Machtinger University of Veterinary Medicine Vienna Surbek, Marta Marta Surbek University of Veterinary Medicine Vienna Pirker, Christine Christine Pirker Medical University of Vienna Kodajova, Petra Petra Kodajova 0000-0003-2746-7631 University of Veterinary Medicine Vienna Timelthaler, Gerald Gerald Timelthaler Medical University of Vienna Schlederer, Michaela Michaela Schlederer Medical University of Vienna Garces de Los Fayos Alonso, Ines Ines Garces de Los Fayos Alonso University of Veterinary Medicine Vienna / Medical University Vienna Braun, Till Till Braun Cologne University Lazzeri, Isaac Isaac Lazzeri Medical University of Graz Spiegl, Benjamin Benjamin Spiegl 0000-0003-4497-6120 Medical University of Graz Graf, Ricarda Ricarda Graf Medical University of Graz Sedighi, Abootaleb Abootaleb Sedighi University of Toronto de Araujo, Elvin D Elvin D de Araujo 0000-0003-0716-2830 University of Toronto Teufelberger, Andrea R Andrea R Teufelberger 0000-0002-1142-949X Medical University of Graz Pölöske, Daniel Daniel Pölöske University of Veterinary Medicine Vienna Dey, Saptaswa Saptaswa Dey 0000-0001-7532-7858 Medical University of Graz Vieyra-Garcia, Pablo Augusto Pablo Augusto Vieyra-Garcia 0000-0001-7101-9313 Medical University of Graz Wiley text eng Leukemic cutaneous T-cell lymphomas (L-CTCL) are lymphoproliferative disorders of skin-homing mature T-cells causing severe symptoms and high mortality through chronic inflammation, tissue destruction, and serious infections. Despite numerous genomic sequencing efforts, recurrent driver mutations have not been identified, but chromosomal losses and gains are frequent and dominant. We integrated genomic landscape analyses with innovative pharmacologic interference studies to identify key vulnerable nodes in L-CTCL. We detected copy number gains of loci containing the STAT3/5 oncogenes in 74% (n = 17/23) of L-CTCL, which correlated with the increased clonal T-cell count in the blood. Dual inhibition of STAT3/5 using small-molecule degraders and multi-kinase blockers abolished L-CTCL cell growth in vitro and ex vivo, whereby PAK kinase inhibition was specifically selective for L-CTCL patient cells carrying STAT3/5 gains. Importantly, the PAK inhibitor FRAx597 demonstrated encouraging anti-leukemic activity in vivo by inhibiting tumor growth and disease dissemination in intradermally xenografted mice. We conclude that STAT3/5 and PAK kinase interaction represents a new therapeutic node to be further explored in L-CTCL. Mycosis-Fungoides; Prognostic-Factors; Sezary-Syndrome; Expression; Apoptosis; Phosphorylation; Resistance; Mutations; Landscape; Growth http://creativecommons.org/licenses/by/4.0/ https://phaidra.vetmeduni.ac.at/api/object/o:1699/download 10.15252/emmm.202115200 https://phaidra.vetmeduni.ac.at/o:605 application/pdf EMBO Molecular Medicine 14(12) (2022) EMBO Molecular Medicine 14 12 1.25 MB 2022