Yu Jian, Chen Yun, Chen Liguang, Zhang Ling, Rassenti Laura Z, Widhopf George F, Kipps Thomas J
Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
Oncotarget. 2018 May 15;9(37):24731-24736. doi: 10.18632/oncotarget.25340.
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 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.
环木单抗（Cirmtuzumab）可能通过抑制慢性淋巴细胞白血病（CLL）患者中ROR1依赖性信号通路来增强依鲁替尼（ibrutinib）的治疗活性。套细胞淋巴瘤（MCL）是一种也表达ROR1的B细胞恶性肿瘤。在本研究中，我们发现MCL患者的血浆中ROR1配体Wnt5a水平很高，与CLL患者中的水平相当；相比之下，在年龄匹配的健康成年人血浆中几乎检测不到Wnt5a。我们还发现Wnt5a可诱导原发性MCL细胞中的Rac1激活。环木单抗而非依鲁替尼能够抑制Wnt5a诱导原发性MCL细胞激活Rac1的能力。在存在CD154和IL-4/10的情况下，随着时间的推移，添加外源性Wnt5a可显著增加MCL细胞的分裂数量以及进入S/G2期的分裂MCL细胞的比例。用环木单抗而非依鲁替尼处理MCL细胞可阻断Wnt5a增强的MCL细胞增殖。本研究表明，环木单抗和依鲁替尼在MCL患者的治疗中可能具有互补活性。
