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

Area of Science:

• Molecular Biology
• Oncology
• Immunology

Background:

• Tyrosine Kinase 2 (TYK2) is integral to cytokine signaling via the JAK/STAT pathway.
• Germline TYK2 mutations (P760L, G761V) in the pseudokinase domain cause constitutive activation and have been linked to acute lymphoblastic leukemia (ALL).

Purpose of the Study:

• To investigate the leukemogenic potential of TYK2 mutations.
• To identify effective therapeutic strategies for TYK2-driven leukemias.

Main Methods:

• Demonstrated the transformation capacity of TYK2 P760L in hematopoietic cells and in vivo models.
• Conducted a kinase inhibitor screen to identify synergistic pathways.
• Tested the efficacy of deucravacitinib in combination with other inhibitors on patient-derived cells.

Main Results:

• TYK2 P760L mutation drives transformation and leukemia development in hematopoietic cells.
• Oncogenic TYK2 cooperates with PI3K/AKT/mTOR and CDK4/6 pathways.
• The TYK2 inhibitor deucravacitinib, when combined with mTOR or CDK4/6 inhibitors, effectively reduces cell viability in TYK2-driven leukemia models.

Conclusions:

• Constitutively active TYK2 mutations are oncogenic and can initiate leukemia.
• Combination therapy targeting TYK2, mTOR, and CDK4/6 pathways represents a novel therapeutic approach for patients with TYK2-driven acute leukemia.