University of Veterinary Medicine Vienna Blocking STAT3/5 through direct or upstream kinase targeting in leukemic cutaneous T-cell lymphoma 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. en TEXT article Mycosis-Fungoides; Prognostic-Factors; Sezary-Syndrome; Expression; Apoptosis; Phosphorylation; Resistance; Mutations; Landscape; Growth 2022 2022 Sorger, Helena (University of Veterinary Medicine, Vienna / Medical University Vienna / University of Vienna) Nguyen, Van Anh (Medical University of Innsbruck) André, Fiona (Medical University of Innsbruck) Nicolay, Jan P. (University Hospital Mannheim) Wobser, Marion (University Hospital Wuerzburg) Berger, Walter (Medical University of Vienna) Orlova, Anna (University of Veterinary Medicine Vienna) Metzelder, Martin L. (Medical University of Vienna) Olaoye, Olasunkanmi O. (University of Toronto) Manaswiyoungkul, Pimyupa (University of Toronto) Abdeldayem, Ayah (University of Toronto) Wolf, Peter (Medical University of Graz) Tin, Gary (University of Toronto) Albrecht, Jana D (University Hospital Mannheim) Otte, Moritz (Cologne University) Ober, Jennifer (Medical University of Graz) Cerroni, Lorenzo (Medical University of Graz) Fink-Puches, Regina (Medical University of Graz) Pan, Yi (Medical University of Graz) Perchthaler, Isabella (Medical University of Graz) Graier, Thomas (Medical University of Graz) Machtinger, Michael (University of Veterinary Medicine Vienna) Kenner, Lukas (University of Veterinary Medicine Vienna) Surbek, Marta (University of Veterinary Medicine Vienna) Pirker, Christine (Medical University of Vienna) Kodajova, Petra (University of Veterinary Medicine Vienna) Timelthaler, Gerald (Medical University of Vienna) Schlederer, Michaela (Medical University of Vienna) Garces de Los Fayos Alonso, Ines (University of Veterinary Medicine Vienna / Medical University Vienna) Braun, Till (Cologne University) Lazzeri, Isaac (Medical University of Graz) Spiegl, Benjamin (Medical University of Graz) Graf, Ricarda (Medical University of Graz) Gunning, Patrick T. (University of Toronto) Sedighi, Abootaleb (University of Toronto) de Araujo, Elvin D (University of Toronto) Teufelberger, Andrea R (Medical University of Graz) Pölöske, Daniel (University of Veterinary Medicine Vienna) Dey, Saptaswa (Medical University of Graz) Vieyra-Garcia, Pablo Augusto (Medical University of Graz) Heitzer, Ellen (Medical University of Graz) Herling, Marco (Cologne University / University of Leipzig) Merkel, Olaf (Medical University of Vienna) Fleck, Roman Neubauer, Heidi A (University of Veterinary Medicine Vienna) Wiley