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Oncogenic TYK2 P760L kinase is effectively targeted by combinatorial TYK2, mTOR and CDK4/6 kinase blockade

Authors :
Katharina Woess
Sabine Macho-Maschler
Dorette S. van Ingen Schenau
Miriam Butler
Caroline Lassnig
Daniel Valcanover
Andrea Poelzl
Katrin Meissl
Barbara Maurer
Tania Brandstoetter
Claus Vogl
Anna Koren
Stefan Kubicek
Anna Orlova
Richard Moriggl
Birgit Strobl
Veronika Sexl
Frank N. van Leeuwen
Roland P. Kuiper
Mathias Mueller
Source :
Haematologica, Vol 108, Iss 4 (2022)
Publication Year :
2022
Publisher :
Ferrata Storti Foundation, 2022.

Abstract

Tyrosine kinase 2 (TYK2) is a member of the Janus kinase/signal transducer and activator of transcription pathway, which is central in cytokine signaling. Previously, germline TYK2 mutations have been described in two patients developing de novo T-cell acute lymphoblastic leukemias (T-ALL) or precursor B-ALL. The mutations (P760L and G761V) are located within the regulatory pseudokinase domain and lead to constitutive activation of TYK2. We demonstrate the transformation capacity of TYK2 P760L in hematopoietic cell systems including primary bone marrow cells. In vivo engraftment of TYK2 P760L-expressing cell lines led to development of leukemia. A kinase inhibitor screen uncovered that oncogenic TYK2 acts synergistically with the PI3K/AKT/mTOR and CDK4/6 pathways. Accordingly, the TYK2-specific inhibitor deucravacitinib (BMS986165) reduces cell viability of TYK2 P760L-transformed cell models and ex vivo cultured TYK2 P760L-mutated patient- derived xenograft cells most efficiently when combined with mTOR or CDK4/6 inhibitors. Our study thereby pioneers novel treatment options for patients suffering from TYK2-driven acute leukemia.

Details

Language :
English
ISSN :
03906078 and 15928721
Volume :
108
Issue :
4
Database :
Directory of Open Access Journals
Journal :
Haematologica
Publication Type :
Academic Journal
Accession number :
edsdoj.16495fc0f1644407926d2399569c73ec
Document Type :
article
Full Text :
https://doi.org/10.3324/haematol.2021.279848