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Blocking STAT3/5 through direct or upstream kinase targeting in leukemic cutaneous T‐cell lymphoma
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 ha...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9727928/ https://www.ncbi.nlm.nih.gov/pubmed/36341492 http://dx.doi.org/10.15252/emmm.202115200 |
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author | Sorger, Helena Dey, Saptaswa Vieyra‐Garcia, Pablo Augusto Pölöske, Daniel Teufelberger, Andrea R de Araujo, Elvin D Sedighi, Abootaleb Graf, Ricarda Spiegl, Benjamin Lazzeri, Isaac Braun, Till Garces de los Fayos Alonso, Ines Schlederer, Michaela Timelthaler, Gerald Kodajova, Petra Pirker, Christine Surbek, Marta Machtinger, Michael Graier, Thomas Perchthaler, Isabella Pan, Yi Fink‐Puches, Regina Cerroni, Lorenzo Ober, Jennifer Otte, Moritz Albrecht, Jana D Tin, Gary Abdeldayem, Ayah Manaswiyoungkul, Pimyupa Olaoye, Olasunkanmi O Metzelder, Martin L Orlova, Anna Berger, Walter Wobser, Marion Nicolay, Jan P André, Fiona Nguyen, Van Anh Neubauer, Heidi A Fleck, Roman Merkel, Olaf Herling, Marco Heitzer, Ellen Gunning, Patrick T Kenner, Lukas Moriggl, Richard Wolf, Peter |
author_facet | Sorger, Helena Dey, Saptaswa Vieyra‐Garcia, Pablo Augusto Pölöske, Daniel Teufelberger, Andrea R de Araujo, Elvin D Sedighi, Abootaleb Graf, Ricarda Spiegl, Benjamin Lazzeri, Isaac Braun, Till Garces de los Fayos Alonso, Ines Schlederer, Michaela Timelthaler, Gerald Kodajova, Petra Pirker, Christine Surbek, Marta Machtinger, Michael Graier, Thomas Perchthaler, Isabella Pan, Yi Fink‐Puches, Regina Cerroni, Lorenzo Ober, Jennifer Otte, Moritz Albrecht, Jana D Tin, Gary Abdeldayem, Ayah Manaswiyoungkul, Pimyupa Olaoye, Olasunkanmi O Metzelder, Martin L Orlova, Anna Berger, Walter Wobser, Marion Nicolay, Jan P André, Fiona Nguyen, Van Anh Neubauer, Heidi A Fleck, Roman Merkel, Olaf Herling, Marco Heitzer, Ellen Gunning, Patrick T Kenner, Lukas Moriggl, Richard Wolf, Peter |
author_sort | Sorger, Helena |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9727928 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-97279282022-12-08 Blocking STAT3/5 through direct or upstream kinase targeting in leukemic cutaneous T‐cell lymphoma Sorger, Helena Dey, Saptaswa Vieyra‐Garcia, Pablo Augusto Pölöske, Daniel Teufelberger, Andrea R de Araujo, Elvin D Sedighi, Abootaleb Graf, Ricarda Spiegl, Benjamin Lazzeri, Isaac Braun, Till Garces de los Fayos Alonso, Ines Schlederer, Michaela Timelthaler, Gerald Kodajova, Petra Pirker, Christine Surbek, Marta Machtinger, Michael Graier, Thomas Perchthaler, Isabella Pan, Yi Fink‐Puches, Regina Cerroni, Lorenzo Ober, Jennifer Otte, Moritz Albrecht, Jana D Tin, Gary Abdeldayem, Ayah Manaswiyoungkul, Pimyupa Olaoye, Olasunkanmi O Metzelder, Martin L Orlova, Anna Berger, Walter Wobser, Marion Nicolay, Jan P André, Fiona Nguyen, Van Anh Neubauer, Heidi A Fleck, Roman Merkel, Olaf Herling, Marco Heitzer, Ellen Gunning, Patrick T Kenner, Lukas Moriggl, Richard Wolf, Peter EMBO Mol Med Articles 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. John Wiley and Sons Inc. 2022-11-07 /pmc/articles/PMC9727928/ /pubmed/36341492 http://dx.doi.org/10.15252/emmm.202115200 Text en © 2022 The Authors. Published under the terms of the CC BY 4.0 license. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Articles Sorger, Helena Dey, Saptaswa Vieyra‐Garcia, Pablo Augusto Pölöske, Daniel Teufelberger, Andrea R de Araujo, Elvin D Sedighi, Abootaleb Graf, Ricarda Spiegl, Benjamin Lazzeri, Isaac Braun, Till Garces de los Fayos Alonso, Ines Schlederer, Michaela Timelthaler, Gerald Kodajova, Petra Pirker, Christine Surbek, Marta Machtinger, Michael Graier, Thomas Perchthaler, Isabella Pan, Yi Fink‐Puches, Regina Cerroni, Lorenzo Ober, Jennifer Otte, Moritz Albrecht, Jana D Tin, Gary Abdeldayem, Ayah Manaswiyoungkul, Pimyupa Olaoye, Olasunkanmi O Metzelder, Martin L Orlova, Anna Berger, Walter Wobser, Marion Nicolay, Jan P André, Fiona Nguyen, Van Anh Neubauer, Heidi A Fleck, Roman Merkel, Olaf Herling, Marco Heitzer, Ellen Gunning, Patrick T Kenner, Lukas Moriggl, Richard Wolf, Peter Blocking STAT3/5 through direct or upstream kinase targeting in leukemic cutaneous T‐cell lymphoma |
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 | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9727928/ https://www.ncbi.nlm.nih.gov/pubmed/36341492 http://dx.doi.org/10.15252/emmm.202115200 |
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