Open AccessOncogenic TYK2 P760L kinase is effectively targeted by combinatorial TYK2, mTOR and CDK4/6 kinase blockade
Author(s) -
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
Publication year - 2022
Publication title -
haematologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.782
H-Index - 142
eISSN - 1592-8721
pISSN - 0390-6078
DOI - 10.3324/haematol.2021.279848
Subject(s) - tyrosine kinase 2 , pi3k/akt/mtor pathway , cancer research , biology , protein kinase b , janus kinase , kinase , signal transduction , microbiology and biotechnology , receptor , platelet derived growth factor receptor , growth factor , genetics
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-ALLs) or precursor B-ALLs. 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 TYK2P760L in hematopoietic cell systems including primary bone marrow cells. In vivo engraftment of TYK2P760L-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 TYK2P760Ltransformed cell models and ex vivo cultured TYK2P760L-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.