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