Anti-adult T‑cell leukemia/lymphoma activity of cerdulatinib, a dual SYK/JAK kinase inhibitor

Abstract

Adult T‑cell leukemia/lymphoma (ATLL) constitutes an aggressive malignancy caused by human T‑cell leukemia virus type 1 (HTLV‑1) that is resistant to available chemotherapeutics. The constitutive activation of Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling is an important feature of ATLL, and spleen tyrosine kinase (SYK) is overexpressed in HTLV‑1-transformed T‑cell lines. In this study, we evaluated the effects of SYK- (PRT060318) or JAK- (JAK inhibitor 1) selective inhibitors and the dual SYK/JAK inhibitor, cerdulatinib, on the viability of HTLV‑1-transformed and ATLL-derived T‑cell lines. Cell proliferation, viability, cell cycle, apoptosis and intracellular signaling cascades were analyzed by the water-soluble tetrazolium-8 assay, flow cytometry and western blot analysis. HTLV‑1-infected T‑cell lines were sensitive to both SYK-selective and pan-JAK inhibitors, whereas cerdulatinib more potently suppressed cell proliferation and reduced cell viability than either of these agents alone. By contrast, the cytotoxic effects of cerdulatinib on uninfected T‑cell lines and peripheral blood mononuclear cells from a healthy donor were less pronounced. Cerdulatinib induced cell cycle arrest in the G2/M phase, which was associated with a decreased cyclin-dependent kinase 1 and cyclin B1, and an increased p21 and p27 expression. Hoechst staining revealed chromatin condensation and nuclear fragmentation in the cells treated with cerdulatinib, and an increased fraction of apoptotic APO2.7-stained cells was detected by flow cytometry. This corresponded to the activation of caspase-8, -9 and -3, and decreased levels of the anti-apoptotic factors, Bcl-xL, survivin, X-linked inhibitor of apoptosis (XIAP) and c‑FLIP. The cerdulatinib-induced decrease in cell viability was partly reversed by the caspase inhibitor, z‑VAD‑FMK. These anti-ATLL effects were associated with the suppression of SYK and JAK/STAT signaling, along with that of the downstream factors, AKT, ERK, activator protein‑1 and nuclear factor-κB. Finally, oral dosing with cerdulatinib lowered the tumor burden in a murine model of ATLL. Thus, our findings indicate that the simultaneous inhibition of therapeutically relevant targets, such as SYK and JAK is a more effective approach than single-agent therapy for the treatment of ATLL.

The Role of Bcl-xL Protein in Viral Infections

“…Another study on ATLL treatment strategies was devoted to the evaluation of cerdulatinib, a chemical agent inhibiting JAK and spleen tyrosine kinase (SYK). Ishikawa et al [112] have determined its anti-proliferative and pro-apoptotic impact on HTLV-1 infected T lymphocytes. The activity of cerdulatinib led to a number of pro-apoptotic events, including a decrease in the intracellular level of Bcl-xL [112].…”

Role of Platelet Glycoprotein VI and Tyrosine Kinase Syk in Thrombus Formation on Collagen-Like Surfaces

“…For this purpose, we used a panel of collagens, collagen peptides, and collagen-H (with established GPVI dependency) and the selective Syk inhibitor PRT-060318 (Syk-IN). The latter compound has recently been used to specify Syk-dependent pathways in mouse platelets [21,25] and in human T cells [26]. As a direct readout of this signaling pathway, we also assessed Syk-dependent rises in cytosolic Ca 2+ .…”

Efficacy of JAK inhibitors in Crohn’s Disease

“…Further JAK inhibitors in clinical development are Cerdulatinib [PRT062070] for haematological malignancies, 43 , 44 Gandotinib [LY-2784544] for myeloproliferative neoplasms, 45 Lestaurtinib [CEP-701] for acute myeloid leukaemia, 46 , 47 Momelotinib [GS-0387, CYT-387] for myeloproliferative disorders, 48 , 49 Pacritinib [SB1518] for relapsed lymphoma and advanced myeloid malignancies, 50 , 51 and PF-04965842 for atopic dermatitis and moderate to severe psoriasis. 52 …”