Blocking STAT3/5 through direct or upstream kinase targeting in leukemic cutaneous T‐cell lymphoma

Blocking STAT3/5 through direct or upstream kinase targeting in leukemic cutaneous T‐cell lymphoma

Abstract 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 mut...

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Main Authors: Helena Sorger, Saptaswa Dey, Pablo Augusto Vieyra‐Garcia, Daniel Pölöske, Andrea R Teufelberger, Elvin D de Araujo, Abootaleb Sedighi, Ricarda Graf, Benjamin Spiegl, Isaac Lazzeri, Till Braun, Ines Garces de los Fayos Alonso, Michaela Schlederer, Gerald Timelthaler, Petra Kodajova, Christine Pirker, Marta Surbek, Michael Machtinger, Thomas Graier, Isabella Perchthaler, Yi Pan, Regina Fink‐Puches, Lorenzo Cerroni, Jennifer Ober, Moritz Otte, Jana D Albrecht, Gary Tin, Ayah Abdeldayem, Pimyupa Manaswiyoungkul, Olasunkanmi O Olaoye, Martin L Metzelder, Anna Orlova, Walter Berger, Marion Wobser, Jan P Nicolay, Fiona André, Van Anh Nguyen, Heidi A Neubauer, Roman Fleck, Olaf Merkel, Marco Herling, Ellen Heitzer, Patrick T Gunning, Lukas Kenner, Richard Moriggl, Peter Wolf
Format: Article
Language:English
Published: Springer Nature 2022-11-01
Series:EMBO Molecular Medicine
Subjects:
lymphoma
STAT3
STAT5
targeting
T‐cell
Online Access:https://doi.org/10.15252/emmm.202115200
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Summary:Abstract 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.
ISSN:1757-4676
1757-4684

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