Kuiatse Isere, Baladandayuthapani Veerabhadran, Lin Heather Y, Thomas Sheeba K, Bjorklund Chad C, Weber Donna M, Wang Michael, Shah Jatin J, Zhang Xing-Ding, Jones Richard J, Ansell Stephen M, Yang Guang, Treon Steven P, Orlowski Robert Z
Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Clin Cancer Res. 2015 Jun 1;21(11):2538-45. doi: 10.1158/1078-0432.CCR-14-1462. Epub 2015 Mar 6.
Waldenström macroglobulinemia (WMG) is a lymphoproliferative disorder characterized by good initial responses to standard therapeutics, but only a minority of patients achieve complete remissions, and most inevitably relapse, indicating a need for novel agents. B-cell receptor signaling has been linked to clonal evolution in WMG, and Spleen tyrosine kinase (Syk) is overexpressed in primary cells, suggesting that it could be a novel and rational target.
We studied the impact of the Syk inhibitor fostamatinib on BCWM.1 and MWCL-1 WMG-derived cell lines both in vitro and in vivo, as well as on primary patient cells.
In WMG-derived cell lines, fostamatinib induced a time- and dose-dependent reduction in viability, associated with activation of apoptosis. At the molecular level, fostamatinib reduced activation of Syk and Bruton's tyrosine kinase, and also downstream signaling through MAPK kinase (MEK), p44/42 MAPK, and protein kinase B/Akt. As a single agent, fostamatinib induced tumor growth delay in an in vivo model of WMG, and reduced viability of primary WMG cells, along with inhibition of p44/42 MAPK signaling. Finally, fostamatinib in combination with other agents, including dexamethasone, bortezomib, and rituximab, showed enhanced activity.
Taken together, these data support the translation of approaches targeting Syk with fostamatinib to the clinic for patients with relapsed and possibly even newly diagnosed WMG.
华氏巨球蛋白血症（WMG）是一种淋巴增殖性疾病，其特点是对标准治疗的初始反应良好，但只有少数患者能达到完全缓解，且大多数患者不可避免地会复发，这表明需要新型药物。B细胞受体信号传导与WMG中的克隆进化有关，脾酪氨酸激酶（Syk）在原代细胞中过表达，提示它可能是一个新的合理靶点。
我们研究了Syk抑制剂福他替尼对BCWM.1和MWCL-1这两种源自WMG的细胞系的体内外影响，以及对患者原代细胞的影响。
在源自WMG的细胞系中，福他替尼诱导细胞活力呈时间和剂量依赖性降低，并伴有细胞凋亡激活。在分子水平上，福他替尼降低了Syk和布鲁顿酪氨酸激酶的激活，以及通过丝裂原活化蛋白激酶激酶（MEK）、p44/42丝裂原活化蛋白激酶和蛋白激酶B/Akt的下游信号传导。作为单一药物，福他替尼在WMG体内模型中诱导肿瘤生长延迟，并降低原代WMG细胞的活力，同时抑制p44/42丝裂原活化蛋白激酶信号传导。最后，福他替尼与其他药物（包括地塞米松、硼替佐米和利妥昔单抗）联合使用时显示出增强的活性。
综上所述，这些数据支持将用福他替尼靶向Syk的方法转化应用于复发甚至可能是新诊断的WMG患者的临床治疗。
