The Bruton tyrosine kinase inhibitor ibrutinib targets interleukin-2 inducible kinase (ITK) in T cells.
Major finding: The Bruton tyrosine kinase inhibitor ibrutinib targets interleukin-2 inducible kinase (ITK) in T cells.
Concept: Irreversible inhibition of ITK by ibrutinib prevents Th2 cell activation and promotes Th1 cell expansion.
Impact: Ibrutinib may be useful in cancers that are driven by ITK or supported by Th2-based immune responses.
Ibrutinib is a small-molecule inhibitor of Bruton tyrosine kinase (BTK) that has shown significant clinical activity in B-cell malignancies. BTK shares significant homology with interleukin-2 inducible kinase (ITK), which acts downstream of the T-cell receptor (TCR). ITK is active in T-cell malignancies and has been linked to tumor immune invasion and survival through its critical role in T helper type 2 (Th2) cell differentiation, making it an attractive therapeutic target. Given the structural homology between BTK and ITK and in silico docking studies suggesting similarities in active site occupancy and covalent binding by ibrutinib, Dubovsky and colleagues hypothesized that ITK might also be an ibrutinib target. Indeed, ibrutinib irreversibly bound ITK both in vitro and in the peripheral blood mononuclear cells of ibrutinib-treated patients. Ibrutinib also inhibited ITK kinase activity in a dose-dependent manner and blocked activation of signaling pathways downstream of ITK upon TCR stimulation. To determine the effect of ibrutinib-mediated ITK inhibition on Th2 cells, naïve CD4 T cells were polarized into Th1 and Th2 cells in vitro and treated with ibrutinib. Ibrutinib inhibited ITK-dependent signaling and cytokine production in Th2 cells, whereas Th1 cells, which express a kinase that can compensate for loss of ITK, were unaffected. Consistent with these findings, prolonged ibrutinib treatment specifically blocked Th2 cell activation and provided selective pressure for expansion of Th1 cells and Th1 cytokine skewing in patients with chronic lymphocytic leukemia (CLL). Ibrutinib-dependent Th1 skewing also reversed CD8+ T cell–mediated immunosuppression and promoted clearance of Listeria monocytogenesinfections in leukemic mice, a notable finding given that infections are the primary cause of death in immunosuppressed patients with CLL. The identification of ibrutinib as an inhibitor of ITK in T cells suggests that this drug could be used more broadly as an immunomodulator or in combination with cancer immunotherapies.
Dubovsky JA, Beckwith KA, Natarajan G, Woyach JA, Jaglowski S, Zhong Y, et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1 selective pressure in T-lymphocytes. Blood 2013 Jul 25 [Epub ahead of print].
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