The JAK inhibitor AZD1480 regulates proliferation and immunity in Hodgkin lymphoma

Abstract

Aberrant activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway has been reported to promote proliferation and survival of Hodgkin and Reed–Sternberg cells of Hodgkin lymphoma (HL). We investigated the activity of the JAK inhibitor AZD1480 in HL-derived cell lines and determined its mechanisms of action. AZD1480 at low doses (0.1–1 μ) potently inhibited STATs phosphorylation, but did not predictably result in antiproliferative effects, as it activated a negative-feedback loop causing phosphorylation of JAK2 and extracellular signal-regulated kinases 1 and 2 (ERK1/2), and increased IP-10, RANTES and interleukin (IL)-8 concentrations in the supernatants. Inhibition of the ERK activity by mitogen-activated extracellular signal regulated kinase (MEK) inhibitors (UO126 and PD98059) enhanced the cytotoxic activity of AZD1480. Interestingly, submicromolar concentrations of AZD1480 demonstrated significant immunoregulatory effects by downregulating T-helper 2 cytokines and chemokines, including IL-13 and thymus- and activation-regulated chemokine, and the surface expression of the immunosuppressive programmed death ligands 1 and 2. Higher concentrations of AZD1480 (5 μ) induced G2/M arrest and cell death by inhibiting Aurora kinases. Our study demonstrates that AZD1480 regulates proliferation and immunity in HL cell lines and provides mechanistic rationale for evaluating AZD1480 alone or in combination with MEK inhibitors in HL.

Immunologic pathomechanism of Hodgkin's lymphoma

“…Inhibitors of the JAK/STAT pathway have been investigated mostly in vitrodspecifically, AZD1480 [97] and lestaurtinib [98]. Targeted therapy against surface receptors of the HRS cells includes anti-RANK ligand antibody and anti-CD80 antibody (galiximab) [99].…”

Endogenous transmembrane protein UT2 inhibits pSTAT3 and suppresses hematological malignancy

“…were from Abcam. AZD1480 (catalog S2162) (64)(65)(66)(67)(68), ruxolitinib (catalog S1378) (69)(70)(71), perifosine (catalog S1037) (72)(73)(74)(75)(76), and MK2206 (catalog S1078) (77)(78)(79) were purchased from Selleckchem. HEK293T, MDA-MB231, T47D, DU145, and PC3 cells were purchased from ATCC.…”

Targeted Therapy in Relapsed Classical Hodgkin Lymphoma

“…Aberrant activation of the JAK/STAT pathway also promotes proliferation and survival of HRS cells, and in vitro studies showed activity of JAK 2 inhibitors in HL 41 A recent phase I trial investigated the novel oral JAK2 inhibitor, SB1518, in patients with R/R HL. The minimum tolerated dose was not reached and treatment was well tolerated; however, no objective responses were seen in HL.…”