Titel (eng)

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

Autor*in

Helena Sorger   University of Veterinary Medicine, Vienna / Medical University Vienna / University of Vienna

Peter Wolf   Medical University of Graz

Lukas Kenner   University of Veterinary Medicine Vienna

Patrick T. Gunning   University of Toronto

Ellen Heitzer   Medical University of Graz

Marco Herling   Cologne University / University of Leipzig

Olaf Merkel   Medical University of Vienna

Roman Fleck

Heidi A Neubauer   University of Veterinary Medicine Vienna

Van Anh Nguyen   Medical University of Innsbruck

Fiona André   Medical University of Innsbruck

Jan P. Nicolay   University Hospital Mannheim

Marion Wobser   University Hospital Wuerzburg

Walter Berger   Medical University of Vienna

Anna Orlova   University of Veterinary Medicine Vienna

Martin L. Metzelder   Medical University of Vienna

Olasunkanmi O. Olaoye   University of Toronto

Pimyupa Manaswiyoungkul   University of Toronto

Ayah Abdeldayem   University of Toronto

Gary Tin   University of Toronto

Jana D Albrecht   University Hospital Mannheim

Moritz Otte   Cologne University

Jennifer Ober   Medical University of Graz

Lorenzo Cerroni   Medical University of Graz

Regina Fink-Puches   Medical University of Graz

Yi Pan   Medical University of Graz

Isabella Perchthaler   Medical University of Graz

Thomas Graier   Medical University of Graz

Michael Machtinger   University of Veterinary Medicine Vienna

Marta Surbek   University of Veterinary Medicine Vienna

Christine Pirker   Medical University of Vienna

Petra Kodajova   University of Veterinary Medicine Vienna

Gerald Timelthaler   Medical University of Vienna

Michaela Schlederer   Medical University of Vienna

Ines Garces de Los Fayos Alonso   University of Veterinary Medicine Vienna / Medical University Vienna

Till Braun   Cologne University

Isaac Lazzeri   Medical University of Graz

Benjamin Spiegl   Medical University of Graz

Ricarda Graf   Medical University of Graz

Abootaleb Sedighi   University of Toronto

Elvin D de Araujo   University of Toronto

Andrea R Teufelberger   Medical University of Graz

Daniel Pölöske   University of Veterinary Medicine Vienna

Saptaswa Dey   Medical University of Graz

Pablo Augusto Vieyra-Garcia   Medical University of Graz

Verlag

Wiley

Beschreibung (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.

Sprache des Objekts

Englisch

Datum

2022

Rechte

Dieses Werk bzw. dieser Inhalt steht unter einer
CC BY 4.0 - Creative Commons Namensnennung 4.0 International Lizenz.

CC BY 4.0 International

http://creativecommons.org/licenses/by/4.0/

Klassifikation

Mycosis-Fungoides; Prognostic-Factors; Sezary-Syndrome; Expression; Apoptosis; Phosphorylation; Resistance; Mutations; Landscape; Growth

Mitglied in der/den Collection(s) (1)