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 Wolf, Peter Peter Wolf 0000-0001-7777-9444 Kenner, Lukas Lukas Kenner 0000-0003-0918-9463 University of Veterinary Medicine Vienna Gunning, Patrick T. Patrick T. Gunning 0000-0003-0654-735X Heitzer, Ellen Ellen Heitzer Herling, Marco Marco Herling Merkel, Olaf Olaf Merkel 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 André, Fiona Fiona André Nicolay, Jan P. Jan P. Nicolay Wobser, Marion Marion Wobser Berger, Walter Walter Berger Orlova, Anna Anna Orlova 0000-0001-9262-7529 University of Veterinary Medicine Vienna Metzelder, Martin L. Martin L. Metzelder Olaoye, Olasunkanmi O. Olasunkanmi O. Olaoye Manaswiyoungkul, Pimyupa Pimyupa Manaswiyoungkul Abdeldayem, Ayah Ayah Abdeldayem Tin, Gary Gary Tin Albrecht, Jana D Jana D Albrecht Otte, Moritz Moritz Otte Ober, Jennifer Jennifer Ober Cerroni, Lorenzo Lorenzo Cerroni Fink-Puches, Regina Regina Fink-Puches Pan, Yi Yi Pan 0000-0001-6723-1370 Perchthaler, Isabella Isabella Perchthaler Graier, Thomas Thomas Graier Machtinger, Michael Michael Machtinger University of Veterinary Medicine Vienna Surbek, Marta Marta Surbek University of Veterinary Medicine Vienna Pirker, Christine Christine Pirker Kodajova, Petra Petra Kodajova 0000-0003-2746-7631 University of Veterinary Medicine Vienna Timelthaler, Gerald Gerald Timelthaler Schlederer, Michaela Michaela Schlederer Garces de Los Fayos Alonso, Ines Ines Garces de Los Fayos Alonso University of Veterinary Medicine Vienna Braun, Till Till Braun Lazzeri, Isaac Isaac Lazzeri Spiegl, Benjamin Benjamin Spiegl 0000-0003-4497-6120 Graf, Ricarda Ricarda Graf Sedighi, Abootaleb Abootaleb Sedighi de Araujo, Elvin D Elvin D de Araujo 0000-0003-0716-2830 Teufelberger, Andrea R Andrea R Teufelberger 0000-0002-1142-949X Pölöske, Daniel Daniel Pölöske University of Veterinary Medicine Vienna Dey, Saptaswa Saptaswa Dey 0000-0001-7532-7858 Vieyra-Garcia, Pablo Augusto Pablo Augusto Vieyra-Garcia 0000-0001-7101-9313 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. lymphoma STAT3 STAT5 targeting T‐cell 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