| Title: |
Oncogenic TYK2P760L kinase is effectively targeted by combinatorial TYK2, mTOR and CDK4/6 kinase blockade |
| Authors: |
Woess, Katharina (University of Veterinary Medicine Vienna); Mueller, Mathias (University of Veterinary Medicine Vienna); Vogl, Claus (University of Veterinary Medicine Vienna); Brandstoetter, Tania (University of Veterinary Medicine Vienna); Maurer, Barbara (University of Veterinary Medicine Vienna); Macho-Maschler, Sabine (University of Veterinary Medicine Vienna); Van Ingen Schenau, Dorette S. (Princess Máxima Center for Pediatric Oncology); Butler, Miriam (Princess Máxima Center for Pediatric Oncology); Lassnig, Caroline (University of Veterinary Medicine Vienna); Valcanover, Daniel (University of Veterinary Medicine Vienna); Poelzl, Andrea (University of Veterinary Medicine Vienna); Meissl, Katrin (University of Veterinary Medicine Vienna); Kuiper, Roland P. (Princess Máxima Center for Pediatric Oncology / University Medical Center Utrecht); Van Leeuwen, Frank N. (Princess Máxima Center for Pediatric Oncology); Sexl, Veronika (University of Veterinary Medicine Vienna); Strobl, Birgit (University of Veterinary Medicine Vienna); Moriggl, Richard (University of Veterinary Medicine Vienna); Orlova, Anna (University of Veterinary Medicine Vienna); Kubicek, Stefan (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences); Koren, Anna (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences) |
| Source: |
Haematologica 108(4), 993-1005 (2023) |
| Publisher Information: |
Ferrata Storti Foundation |
| Publication Year: |
2023 |
| Subject Terms: |
Acute Lymphoblastic-Leukemia; Jak-Stat Pathway; Cell-Cycle; Preclinical Characterization; Selective Inhibitor; Activation; Cancer; Mutations; Jak/Stat; Lesions |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
isPartOf:https://phaidra.vetmeduni.ac.at/o:605[Open Access Publications]; https://phaidra.vetmeduni.ac.at/o:2234 |
| DOI: |
10.3324/haematol.2021.279848 |
| Availability: |
https://doi.org/10.3324/haematol.2021.279848; https://phaidra.vetmeduni.ac.at/o:2234 |
| Rights: |
CC BY-NC 4.0 International ; http://creativecommons.org/licenses/by-nc/4.0/ |
| Accession Number: |
edsbas.281043D0 |
| Database: |
BASE |