Mapatumumab and lexatumumab induce apoptosis in TRAIL-R1 and TRAIL-R2 antibody-resistant NSCLC cell lines when treated in combination with bortezomib
Mapatumumab and lexatumumab induce apoptosis in TRAIL-R1 and TRAIL-R2 antibody-resistant NSCLC cell lines when treated in combination with bortezomib
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DOI：
10.1158/1535-7163.mct-08-0918
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发表时间：
2009-02-01
影响因子：
5.7
通讯作者：
Humphreys, Robin
中科院分区：
文献类型：
--
作者：
Luster, Troy A.;Carrel, Jeffrey A.;Humphreys, Robin
Mapatumumab 和 lexatumumab 是完全人源单克隆抗体，分别结合并激活人肿瘤坏死因子相关凋亡诱导配体受体 1 和 2。这些抗体诱导各种肿瘤细胞类型的细胞凋亡，尽管敏感性程度可以从高度敏感到完全耐药。重要的是，对马帕木单抗或雷克妥木单抗部分或完全耐药的肿瘤细胞在与化疗药物联合治疗时通常会变得敏感。在这方面，蛋白酶体抑制剂硼替佐米（bortezomib）最近与马帕木单抗（mapatumumab）和雷克妥木单抗（lexatumumab）联合使用时，显示出针对已建立的淋巴瘤细胞系和原发性淋巴瘤的协同活性。在这里，我们使用一组人类非小细胞肺癌（NSCLC）细胞系报告了类似的发现。具体来说，我们表明，硼替佐尼快速诱导对单独抗体完全耐药的 NSCLC 细胞系中对马帕木单抗和 lexatumumab 的敏感性，并且低至 25 nmol/L 的硼替佐米浓度使 NSCLC 细胞对抗体敏感。此外，测试浓度的硼替佐米单独作用极小，表明该组合产生协同细胞毒性。联合治疗诱导 caspase 级联的激活，并且联合治疗的效果是 caspase 依赖性的。硼替佐米治疗增加了几种重要的细胞凋亡调节剂的细胞内水平，这些调节剂可能介导对马帕木单抗和雷克妥木单抗的敏感性增强。这些结果表明，未来对 NSCLC 患者中马帕木单抗或莱沙木单抗联合硼替佐米进行评估是有必要的。 [摩尔癌症疗法 2009;8(2):292 - 302]
Mapatumumab and lexatumumab are fully human monoclonal antibodies that bind and activate human tumor necrosis factor-related apoptosis-inducing ligand receptors 1 and 2, respectively. These antibodies induce apoptosis in various tumor cell types, although the degree of sensitivity can vary from highly sensitive to completely resistant. Importantly, tumor cells that are partially or completely resistant to mapatumumab or lexatumumab can often be sensitized when treated in combination with chemotherapeutic drugs. In this regard, the proteasome inhibitor bortezomib has recently shown synergistic activity against established lymphoma cell lines and primary lymphomas when combined with mapatumumab and lexatumumab. Here, we report similar findings using a panel of human non-small cell lung cancer (NSCLC) cell lines. Specifically, we show that bortezonnib rapidly induces sensitivity to mapatumumab and lexatumumab in NSCLC cell lines that are completely resistant to antibody alone and that bortezomib concentrations as low as 25 nmol/L sensitize NSCLC cells to the antibodies. Furthermore, bortezomib at the tested concentration has minimal effect on its own, indicating the combination generates synergistic cytotoxicity. Combination treatment induces activation of the caspase cascade and the effect of the combination is caspase dependent. Bortezomib treatment increases the intracellular levels of several important apoptosis regulators that may mediate enhanced sensitivity to mapatumumab and lexatumumab. These results suggest future evaluation of mapatumumab or lexatumumab in combination with bortezomib is warranted in NSCLC patients. [Mol Cancer Ther 2009;8(2):292 - 302]