Abstract
Cirmtuzumab may enhance the therapeutic activity of ibrutinib by inhibiting ROR1-dependent signaling pathway in patients with chronic lymphocytic leukemia (CLL). Mantle cell lymphoma (MCL) is B-cell malignancy that also expresses ROR1. In this study, we found that the plasma of patients with MCL had high levels of Wnt5a, a ROR1 ligand, that were comparable to those found in patients with CLL; in contrast Wnt5a was virtually undetectable in the plasma of age-matched healthy adults. We also found that Wnt5a induced Rac1 activation in the primary MCL cells. Cirmtuzumab, but not ibrutinib, could inhibit the capacity of Wnt5a to induce primary MCL cells to activate Rac1. Addition of exogenous Wnt5a in vitro significantly enhanced the numbers of MCL cell divisions and the proportion of dividing MCL cells entering S/G2 in MCL cells over time in the presence of CD154 and IL-4/10. Treatment of the MCL cells with cirmtuzumab, but not ibrutinib, blocked Wnt5a-enhanced proliferation of MCL cells. This study indicates that cirmtuzumab and ibrutinib may have complementary activity in the treatment of patients with MCL.
Highlights
Recent studies have demonstrated that Wnt5a could induce activation of Rac1 in leukemia cells of patients with chronic lymphocytic leukemia (CLL) via a ROR1-dependent pathway [1], which could not be inhibited by ibrutinib [2]
We found that the plasma of patients with Mantle cell lymphoma (MCL) had high levels of Wnt5a, a ROR1 ligand, that were comparable to those found in patients with CLL; in contrast Wnt5a was virtually undetectable in the plasma of age-matched healthy adults
This revealed that Wnt5a induced Rac1 activation in the primary MCL cells and that this effect could be blocked by cirmtuzumab, but not ibrutinib, as observed with primary CLL cells (Figure 1C–1D)
Summary
Recent studies have demonstrated that Wnt5a could induce activation of Rac in leukemia cells of patients with CLL via a ROR1-dependent pathway [1], which could not be inhibited by ibrutinib [2]. Wnt5a could induce Rac activation to enhance proliferation and survival of ROR1expressing CLL cells, even when treated with ibrutinib at concentrations that were effective in inhibiting BTK and B-cell-receptor (BCR) signaling [2]. Such Wnt5a-induced Rac activation could be blocked by cirmtuzumab (UC-961), a humanized anti-ROR1 mAb, which is undergoing clinical evaluation in patients with CLL [3]. Mantle cell lymphoma (MCL) is B cell malignancy that expresses ROR1 [4] It is not known whether Wnt5a can induce Rac activation in MCL or whether such activation is affected by treatment with either ibrutinib or cirmtuzumab. This signaling-pathway cannot be blocked by ibrutinib, even at concentrations that completely inhibit BTK or BCR-signaling
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