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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2022-12-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202115200 |
| _version_ | 1797285756344991744 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Helena Sorger |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-07T18:06:52Z |
| format | Article |
| id | doaj.art-c1ee8bac3c164d9b80fc189cf3bc69bf |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T18:06:52Z |
| publishDate | 2022-12-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-c1ee8bac3c164d9b80fc189cf3bc69bf2024-03-02T08:44:39ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842022-12-011412n/an/a10.15252/emmm.202115200Blocking STAT3/5 through direct or upstream kinase targeting in leukemic cutaneous T‐cell lymphomaHelena Sorger0Saptaswa Dey1Pablo Augusto Vieyra‐Garcia2Daniel Pölöske3Andrea R Teufelberger4Elvin D deAraujo5Abootaleb Sedighi6Ricarda Graf7Benjamin Spiegl8Isaac Lazzeri9Till Braun10Ines Garces de los Fayos Alonso11Michaela Schlederer12Gerald Timelthaler13Petra Kodajova14Christine Pirker15Marta Surbek16Michael Machtinger17Thomas Graier18Isabella Perchthaler19Yi Pan20Regina Fink‐Puches21Lorenzo Cerroni22Jennifer Ober23Moritz Otte24Jana D Albrecht25Gary Tin26Ayah Abdeldayem27Pimyupa Manaswiyoungkul28Olasunkanmi O Olaoye29Martin L Metzelder30Anna Orlova31Walter Berger32Marion Wobser33Jan P Nicolay34Fiona André35Van Anh Nguyen36Heidi A Neubauer37Roman Fleck38Olaf Merkel39Marco Herling40Ellen Heitzer41Patrick T Gunning42Lukas Kenner43Richard Moriggl44Peter Wolf45Unit of Functional Cancer Genomics, Institute of Animal Breeding and Genetics University of Veterinary Medicine Vienna AustriaDepartment of Dermatology and Venereology Medical University of Graz Graz AustriaDepartment of Dermatology and Venereology Medical University of Graz Graz AustriaUnit of Functional Cancer Genomics, Institute of Animal Breeding and Genetics University of Veterinary Medicine Vienna AustriaDepartment of Dermatology and Venereology Medical University of Graz Graz AustriaDepartment of Chemical and Physical Sciences University of Toronto Mississauga Mississauga ON CanadaDepartment of Chemical and Physical Sciences University of Toronto Mississauga Mississauga ON CanadaDiagnostic & Research Center for Molecular Bio‐Medicine, Institute of Human Genetics Medical University of Graz Graz AustriaDiagnostic & Research Center for Molecular Bio‐Medicine, Institute of Human Genetics Medical University of Graz Graz AustriaDiagnostic & Research Center for Molecular Bio‐Medicine, Institute of Human Genetics Medical University of Graz Graz AustriaDepartment of Medicine I CIO‐ABCD, CECAD and CMMC Cologne University Cologne GermanyDepartment of Pathology Medical University of Vienna Vienna AustriaDepartment of Pathology Medical University of Vienna Vienna AustriaCentre for Cancer Research Medical University of Vienna Vienna AustriaUnit of Laboratory Animal Pathology University of Veterinary Medicine Vienna Vienna AustriaCentre for Cancer Research Medical University of Vienna Vienna AustriaUnit of Functional Cancer Genomics, Institute of Animal Breeding and Genetics University of Veterinary Medicine Vienna AustriaUnit of Functional Cancer Genomics, Institute of Animal Breeding and Genetics University of Veterinary Medicine Vienna AustriaDepartment of Dermatology and Venereology Medical University of Graz Graz AustriaDepartment of Dermatology and Venereology Medical University of Graz Graz AustriaDepartment of Dermatology and Venereology Medical University of Graz Graz AustriaDepartment of Dermatology and Venereology Medical University of Graz Graz AustriaDepartment of Dermatology and Venereology Medical University of Graz Graz AustriaCore Facility Flow Cytometry, Center for Medical Research (ZMF) Medical University of Graz Graz AustriaDepartment of Medicine I CIO‐ABCD, CECAD and CMMC Cologne University Cologne GermanyDepartment of Dermatology University Hospital Mannheim Mannheim GermanyDepartment of Chemical and Physical Sciences University of Toronto Mississauga Mississauga ON CanadaDepartment of Chemical and Physical Sciences University of Toronto Mississauga Mississauga ON CanadaDepartment of Chemical and Physical Sciences University of Toronto Mississauga Mississauga ON CanadaDepartment of Chemical and Physical Sciences University of Toronto Mississauga Mississauga ON CanadaDepartment of Pediatric and Adolescent Surgery, Vienna General Hospital Medical University of Vienna Vienna AustriaUnit of Functional Cancer Genomics, Institute of Animal Breeding and Genetics University of Veterinary Medicine Vienna AustriaCentre for Cancer Research Medical University of Vienna Vienna AustriaDepartment of Dermatology University Hospital Wuerzburg Wuerzburg GermanyDepartment of Dermatology University Hospital Mannheim Mannheim GermanyUniversity Clinic for Dermatology, Venereology and Allergology Innsbruck Medical University of Innsbruck Innsbruck AustriaUniversity Clinic for Dermatology, Venereology and Allergology Innsbruck Medical University of Innsbruck Innsbruck AustriaUnit of Functional Cancer Genomics, Institute of Animal Breeding and Genetics University of Veterinary Medicine Vienna AustriaJanpix, a Centessa Company London UKDepartment of Pathology Medical University of Vienna Vienna AustriaDepartment of Medicine I CIO‐ABCD, CECAD and CMMC Cologne University Cologne GermanyDiagnostic & Research Center for Molecular Bio‐Medicine, Institute of Human Genetics Medical University of Graz Graz AustriaDepartment of Chemical and Physical Sciences University of Toronto Mississauga Mississauga ON CanadaDepartment of Pathology Medical University of Vienna Vienna AustriaUnit of Functional Cancer Genomics, Institute of Animal Breeding and Genetics University of Veterinary Medicine Vienna AustriaDepartment of Dermatology and Venereology Medical University of Graz Graz AustriaAbstract 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.https://doi.org/10.15252/emmm.202115200lymphomaSTAT3STAT5targetingT‐cell |
| spellingShingle | 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 Blocking STAT3/5 through direct or upstream kinase targeting in leukemic cutaneous T‐cell lymphoma EMBO Molecular Medicine lymphoma STAT3 STAT5 targeting T‐cell |
| title | Blocking STAT3/5 through direct or upstream kinase targeting in leukemic cutaneous T‐cell lymphoma |
| title_full | Blocking STAT3/5 through direct or upstream kinase targeting in leukemic cutaneous T‐cell lymphoma |
| title_fullStr | Blocking STAT3/5 through direct or upstream kinase targeting in leukemic cutaneous T‐cell lymphoma |
| title_full_unstemmed | Blocking STAT3/5 through direct or upstream kinase targeting in leukemic cutaneous T‐cell lymphoma |
| title_short | Blocking STAT3/5 through direct or upstream kinase targeting in leukemic cutaneous T‐cell lymphoma |
| title_sort | blocking stat3 5 through direct or upstream kinase targeting in leukemic cutaneous t cell lymphoma |
| topic | lymphoma STAT3 STAT5 targeting T‐cell |
| url | https://doi.org/10.15252/emmm.202115200 |
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