Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA.
Clin Cancer Res. 2012 Dec 15;18(24):6609-22. doi: 10.1158/1078-0432.CCR-12-1532. Epub 2012 Oct 9.
The TORC1 inhibitor everolimus has previously shown significant activity as a single agent in hematologic malignancies, with reported responses of 30% to 70% in Waldenstrom macroglobulinemia. However, the specific mechanisms by which this class of mTOR inhibitors exerts anti-Waldenstrom macroglobulinemia activity have not been fully investigated. We therefore sought to dissect the mechanisms of everolimus-dependent modulation of Waldenstrom macroglobulinemia cell survival.
We confirmed that everolimus targets mTOR in patients treated with everolimus and responding to therapy. We evaluated the effect of everolimus on proliferation and survival of primary Waldenstrom macroglobulinemia cells, as well as of other IgM-secreting lymphoma cell lines. Everolimus-dependent mechanisms of induced apoptosis and its effect on Waldenstrom macroglobulinemia cells in the context of bone marrow microenvironment have been also evaluated. miRNA-155 loss-of-function studies were conducted. Moreover, the combinatory effect of bortezomib and rituximab has been tested.
We showed that everolimus targeted mTOR downstream signaling pathways, ex vivo, in patients responding to everolimus treatment. Everolimus induced toxicity in primary Waldenstrom macroglobulinemia cells, as well as in other IgM-secreting lymphoma cells, supported by cell-cycle arrest and caspase-dependent and -independent induction of apoptosis. Importantly, everolimus targeted Waldenstrom macroglobulinemia cells even in the context of bone marrow milieu, where it affected migration, adhesion, and angiogenesis. Everolimus-dependent anti-Waldenstrom macroglobulinemia activity was partially driven by miRNA-155. Moreover, everolimus synergized with bortezomib and rituximab in targeting Waldenstrom macroglobulinemia cells, as shown by synergistic inhibition of p65/ and p50/NF-κB activities.
These findings provide a better understanding of the mechanisms that are responsible for everolimus-induced anti-Waldenstrom macroglobulinemia activity.
TORC1 抑制剂依维莫司在血液恶性肿瘤中作为单一药物具有显著的活性，在华氏巨球蛋白血症中的反应率为 30%至 70%。然而，这类 mTOR 抑制剂发挥抗华氏巨球蛋白血症活性的确切机制尚未得到充分研究。因此，我们试图剖析依维莫司依赖的华氏巨球蛋白血症细胞存活调节的机制。
我们证实依维莫司在接受依维莫司治疗且对治疗有反应的患者中靶向 mTOR。我们评估了依维莫司对原代华氏巨球蛋白血症细胞增殖和存活的影响，以及其他 IgM 分泌淋巴瘤细胞系。还评估了依维莫司依赖性诱导细胞凋亡的机制及其对骨髓微环境中的华氏巨球蛋白血症细胞的影响。进行了 miRNA-155 功能丧失研究。此外，还测试了硼替佐米和利妥昔单抗的联合效应。
我们表明，依维莫司在对依维莫司治疗有反应的患者中靶向 mTOR 下游信号通路。依维莫司诱导原代华氏巨球蛋白血症细胞以及其他 IgM 分泌淋巴瘤细胞产生毒性，这是通过细胞周期停滞和半胱天冬酶依赖性和非依赖性诱导凋亡来支持的。重要的是，即使在骨髓环境中，依维莫司也靶向华氏巨球蛋白血症细胞，影响其迁移、黏附和血管生成。依维莫司依赖的抗华氏巨球蛋白血症活性部分由 miRNA-155 驱动。此外，依维莫司与硼替佐米和利妥昔单抗协同作用，靶向华氏巨球蛋白血症细胞，表现为 p65/和 p50/NF-κB 活性的协同抑制。
这些发现为理解依维莫司诱导的抗华氏巨球蛋白血症活性的机制提供了更好的认识。
