EMBO Molecular Medicine (Nov 2022)
Blocking STAT3/5 through direct or upstream kinase targeting in leukemic cutaneous T‐cell lymphoma
- 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
Affiliations
- Helena Sorger
- Unit of Functional Cancer Genomics, Institute of Animal Breeding and Genetics, University of Veterinary Medicine
- Saptaswa Dey
- Department of Dermatology and Venereology, Medical University of Graz
- Pablo Augusto Vieyra‐Garcia
- Department of Dermatology and Venereology, Medical University of Graz
- Daniel Pölöske
- Unit of Functional Cancer Genomics, Institute of Animal Breeding and Genetics, University of Veterinary Medicine
- Andrea R Teufelberger
- Department of Dermatology and Venereology, Medical University of Graz
- Elvin D de Araujo
- Department of Chemical and Physical Sciences, University of Toronto Mississauga
- Abootaleb Sedighi
- Department of Chemical and Physical Sciences, University of Toronto Mississauga
- Ricarda Graf
- Diagnostic & Research Center for Molecular Bio‐Medicine, Institute of Human Genetics, Medical University of Graz
- Benjamin Spiegl
- Diagnostic & Research Center for Molecular Bio‐Medicine, Institute of Human Genetics, Medical University of Graz
- Isaac Lazzeri
- Diagnostic & Research Center for Molecular Bio‐Medicine, Institute of Human Genetics, Medical University of Graz
- Till Braun
- Department of Medicine I, CIO‐ABCD, CECAD and CMMC Cologne University
- Ines Garces de los Fayos Alonso
- Department of Pathology, Medical University of Vienna
- Michaela Schlederer
- Department of Pathology, Medical University of Vienna
- Gerald Timelthaler
- Centre for Cancer Research, Medical University of Vienna
- Petra Kodajova
- Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna
- Christine Pirker
- Centre for Cancer Research, Medical University of Vienna
- Marta Surbek
- Unit of Functional Cancer Genomics, Institute of Animal Breeding and Genetics, University of Veterinary Medicine
- Michael Machtinger
- Unit of Functional Cancer Genomics, Institute of Animal Breeding and Genetics, University of Veterinary Medicine
- Thomas Graier
- Department of Dermatology and Venereology, Medical University of Graz
- Isabella Perchthaler
- Department of Dermatology and Venereology, Medical University of Graz
- Yi Pan
- Department of Dermatology and Venereology, Medical University of Graz
- Regina Fink‐Puches
- Department of Dermatology and Venereology, Medical University of Graz
- Lorenzo Cerroni
- Department of Dermatology and Venereology, Medical University of Graz
- Jennifer Ober
- Core Facility Flow Cytometry, Center for Medical Research (ZMF), Medical University of Graz
- Moritz Otte
- Department of Medicine I, CIO‐ABCD, CECAD and CMMC Cologne University
- Jana D Albrecht
- Department of Dermatology, University Hospital Mannheim
- Gary Tin
- Department of Chemical and Physical Sciences, University of Toronto Mississauga
- Ayah Abdeldayem
- Department of Chemical and Physical Sciences, University of Toronto Mississauga
- Pimyupa Manaswiyoungkul
- Department of Chemical and Physical Sciences, University of Toronto Mississauga
- Olasunkanmi O Olaoye
- Department of Chemical and Physical Sciences, University of Toronto Mississauga
- Martin L Metzelder
- Department of Pediatric and Adolescent Surgery, Vienna General Hospital, Medical University of Vienna
- Anna Orlova
- Unit of Functional Cancer Genomics, Institute of Animal Breeding and Genetics, University of Veterinary Medicine
- Walter Berger
- Centre for Cancer Research, Medical University of Vienna
- Marion Wobser
- Department of Dermatology, University Hospital Wuerzburg
- Jan P Nicolay
- Department of Dermatology, University Hospital Mannheim
- Fiona André
- University Clinic for Dermatology, Venereology and Allergology Innsbruck, Medical University of Innsbruck
- Van Anh Nguyen
- University Clinic for Dermatology, Venereology and Allergology Innsbruck, Medical University of Innsbruck
- Heidi A Neubauer
- Unit of Functional Cancer Genomics, Institute of Animal Breeding and Genetics, University of Veterinary Medicine
- Roman Fleck
- Janpix, a Centessa Company
- Olaf Merkel
- Department of Pathology, Medical University of Vienna
- Marco Herling
- Department of Medicine I, CIO‐ABCD, CECAD and CMMC Cologne University
- Ellen Heitzer
- Diagnostic & Research Center for Molecular Bio‐Medicine, Institute of Human Genetics, Medical University of Graz
- Patrick T Gunning
- Department of Chemical and Physical Sciences, University of Toronto Mississauga
- Lukas Kenner
- Department of Pathology, Medical University of Vienna
- Richard Moriggl
- Unit of Functional Cancer Genomics, Institute of Animal Breeding and Genetics, University of Veterinary Medicine
- Peter Wolf
- Department of Dermatology and Venereology, Medical University of Graz
- DOI
- https://doi.org/10.15252/emmm.202115200
- Journal volume & issue
-
Vol. 14,
no. 12
pp. 1 – 23
Abstract
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.
Keywords
