Comparison of interleukin-2-inducible kinase (ITK) inhibitors and potential for combination therapies for T-cell lymphoma

Patients with peripheral T-cell lymphomas generally have poor clinical outcomes with conventional chemotherapy. Recent advances have demonstrated that a large subgroup of PTCL are derived from follicular helper (Tfh) T-cells. These cases show a characteristic pattern of gene expression, which includes high-level protein expression of interleukin-2-inducible kinase (ITK). ITK is a member of the TEC family of kinases and normally has essential functions in regulating T-cell receptor signalling and T-cell differentiation. Here we report a side-by-side comparison of four ITK inhibitors. We investigate effects on apoptosis, phosphorylation of signaling molecules, calcium flux and migration. In line with a specific mechanism of action ONO7790500 and BMS509744 did not inhibit MEK1/2 or AKT phosphorylation although other ITK inhibitors, ibrutinib and PF-06465469, did have this effect. Specific ITKi had modest effects on apoptosis alone but there was definite synergy with doxorubicin, pictilisib (PI3Ki) and idelalisib (PI3Kδi). ITKi repressed migration of Jurkat cells caused by CXCL12 and the CXCR4 antagonist, plerixafor enhanced this effect. Overall ITKi may have several mechanisms of action that will be therapeutically useful in PTCL including reduction in survival and perturbation of trafficking.