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

Autor: Sorger H; Unit of Functional Cancer Genomics, Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.; Department of Pediatric and Adolescent Surgery, Vienna General Hospital, Medical University of Vienna, Vienna, Austria., Dey S; Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria.; Department of Pathology, Medical University of Vienna, Vienna, Austria., Vieyra-Garcia PA; Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria., Pölöske D; Unit of Functional Cancer Genomics, Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria., Teufelberger AR; Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria., de Araujo ED; Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, ON, Canada.; Centre for Medicinal Chemistry, University of Toronto Mississauga, Mississauga, ON, Canada., Sedighi A; Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, ON, Canada.; Centre for Medicinal Chemistry, University of Toronto Mississauga, Mississauga, ON, Canada., Graf R; Diagnostic & Research Center for Molecular Bio-Medicine, Institute of Human Genetics, Medical University of Graz, Graz, Austria., Spiegl B; Diagnostic & Research Center for Molecular Bio-Medicine, Institute of Human Genetics, Medical University of Graz, Graz, Austria., Lazzeri I; Diagnostic & Research Center for Molecular Bio-Medicine, Institute of Human Genetics, Medical University of Graz, Graz, Austria., Braun T; Department of Medicine I, CIO-ABCD, CECAD and CMMC Cologne University, Cologne, Germany., Garces de Los Fayos Alonso I; Department of Pathology, Medical University of Vienna, Vienna, Austria.; Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, Austria., Schlederer M; Department of Pathology, Medical University of Vienna, Vienna, Austria., Timelthaler G; Centre for Cancer Research, Medical University of Vienna, Vienna, Austria., Kodajova P; Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, Austria., Pirker C; Centre for Cancer Research, Medical University of Vienna, Vienna, Austria.; Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria., Surbek M; Unit of Functional Cancer Genomics, Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria., Machtinger M; Unit of Functional Cancer Genomics, Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria., Graier T; Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria., Perchthaler I; Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria., Pan Y; Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria., Fink-Puches R; Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria., Cerroni L; Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria., Ober J; Core Facility Flow Cytometry, Center for Medical Research (ZMF), Medical University of Graz, Graz, Austria., Otte M; Department of Medicine I, CIO-ABCD, CECAD and CMMC Cologne University, Cologne, Germany., Albrecht JD; Department of Dermatology, University Hospital Mannheim, Mannheim, Germany., Tin G; Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, ON, Canada.; Centre for Medicinal Chemistry, University of Toronto Mississauga, Mississauga, ON, Canada., Abdeldayem A; Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, ON, Canada.; Centre for Medicinal Chemistry, University of Toronto Mississauga, Mississauga, ON, Canada., Manaswiyoungkul P; Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, ON, Canada.; Centre for Medicinal Chemistry, University of Toronto Mississauga, Mississauga, ON, Canada., Olaoye OO; Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, ON, Canada.; Centre for Medicinal Chemistry, University of Toronto Mississauga, Mississauga, ON, Canada., Metzelder ML; Department of Pediatric and Adolescent Surgery, Vienna General Hospital, Medical University of Vienna, Vienna, Austria., Orlova A; Unit of Functional Cancer Genomics, Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria., Berger W; Centre for Cancer Research, Medical University of Vienna, Vienna, Austria.; Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria., Wobser M; Department of Dermatology, University Hospital Wuerzburg, Wuerzburg, Germany., Nicolay JP; Department of Dermatology, University Hospital Mannheim, Mannheim, Germany., André F; University Clinic for Dermatology, Venereology and Allergology Innsbruck, Medical University of Innsbruck, Innsbruck, Austria., Nguyen VA; University Clinic for Dermatology, Venereology and Allergology Innsbruck, Medical University of Innsbruck, Innsbruck, Austria., Neubauer HA; Unit of Functional Cancer Genomics, Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria., Fleck R; Janpix, a Centessa Company, London, UK., Merkel O; Department of Pathology, Medical University of Vienna, Vienna, Austria., Herling M; Department of Medicine I, CIO-ABCD, CECAD and CMMC Cologne University, Cologne, Germany.; Department of Hematology, Cellular Therapy, and Hemostaseology, University of Leipzig, Leipzig, Germany., Heitzer E; Diagnostic & Research Center for Molecular Bio-Medicine, Institute of Human Genetics, Medical University of Graz, Graz, Austria., Gunning PT; Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, ON, Canada.; Centre for Medicinal Chemistry, University of Toronto Mississauga, Mississauga, ON, Canada.; Janpix, a Centessa Company, London, UK., Kenner L; Department of Pathology, Medical University of Vienna, Vienna, Austria.; Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, Austria.; Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.; Christian Doppler Laboratory for Applied Metabolomics (CDL-AM), Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria.; CBmed GmbH Center for Biomarker Research in Medicine, Graz, Austria., Moriggl R; Unit of Functional Cancer Genomics, Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria., Wolf P; Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria.; BioTechMed Graz, Graz, Austria.
Jazyk: angličtina
Zdroj: EMBO molecular medicine [EMBO Mol Med] 2022 Dec 07; Vol. 14 (12), pp. e15200. Date of Electronic Publication: 2022 Nov 07.
DOI: 10.15252/emmm.202115200
Abstrakt: 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.
(© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)
Databáze: MEDLINE
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