Aurora A inhibitor (MLN8237) plus vincristine plus rituximab is synthetic lethal and a potential curative therapy in aggressive B-cell non-Hodgkin lymphoma.
Aurora A inhibitor (MLN8237) plus vincristine plus rituximab is synthetic lethal and a potential curative therapy in aggressive B-cell non-Hodgkin lymphoma.
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DOI：
10.1158/1078-0432.ccr-11-2413
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发表时间：
2012-04-15
期刊：
影响因子：
--
通讯作者：
Qi W
中科院分区：
文献类型：
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作者：
Mahadevan D;Stejskal A;Cooke LS;Manziello A;Morales C;Persky DO;Fisher RI;Miller TP;Qi W
Aurora A和B是调节有丝分裂的致癌丝氨酸/苏氨酸激酶。Auroras的过表达促进对微管靶向剂的抗性。我们研究了MLN 8237 [M]（Aurora A抑制剂）与长春新碱[MV]或多西他赛[MD]在侵袭性B-NHL中抑制有丝分裂纺锤体的协同机制。评价了将利妥昔单抗[R]加入MV或MD的合成致死率。通过分析细胞增殖、细胞凋亡、肿瘤生长、存活和反应/复发机制，通过基因表达谱和蛋白质验证，在体外和体内评价侵袭性B-NHL细胞亚型的靶向调节和单药、双药和三联药的抗NHL活性。在B-NHL细胞培养模型中，MV是协同的，而MD是细胞增殖抑制的加和。在MV中加入R比MD好上级，但与双联体治疗相比，两者均显著诱导细胞凋亡。套细胞淋巴瘤的小鼠异种移植模型显示出对M、R、D和V的适度单药活性，肿瘤生长抑制（TGI）约为10- 15%。在双联体中，MV导致肿瘤消退，而TGI分别与MD（~55-60%）和MR（~25-50%）一起观察到。虽然MV导致肿瘤消退，但小鼠在停止治疗后20天复发。相比之下，MVR是治愈性的，而MDR导致TGI约为85%。收获的肿瘤的PCNA、Aurora B、细胞周期蛋白B1、细胞周期蛋白D1和Bcl-2蛋白证实了对治疗的反应和抗性。在MV中加入R是一种治疗侵袭性B-NHL的新策略，值得临床试验评估。
Aurora A and B are oncogenic serine/threonine kinases that regulate mitosis. Over-expression of Auroras promotes resistance to microtubule targeted agents. We investigated mechanistic synergy by inhibiting the mitotic spindle apparatus in the presence of MLN8237 [M], an Aurora A inhibitor with either vincristine [MV] or docetaxel [MD] in aggressive B-NHL. The addition of rituximab [R] to MV or MD was evaluated for synthetic lethality. Aggressive B-NHL cell subtypes were evaluated in vitro and in vivo for target modulation and anti-NHL activity with single agents, doublets and triplets by analyzing cell proliferation, apoptosis, tumor growth, survival and mechanisms of response/relapse by gene expression profiling with protein validation. MV is synergistic while MD is additive for cell proliferation inhibition in B-NHL cell culture models. Addition of R to MV is superior to MD but both significantly induce apoptosis compared to doublet therapy. Mouse xenograft models of mantle cell lymphoma showed modest single agent activity for M, R, D and V with tumor growth inhibition (TGI) of ~10–15%. Of the doublets, MV caused tumor regression, while TGI was observed with MD (~55–60%) and MR (~25–50%) respectively. Although MV caused tumor regression, mice relapsed 20 days after stopping therapy. In contrast, MVR was curative, while MDR led to TGI of ~85%. PCNA, Aurora B, cyclin B1, cyclin D1 and Bcl-2 proteins of harvested tumors confirmed response and resistance to therapy. Addition of R to MV is a novel therapeutic strategy for aggressive B-NHL and warrants clinical trial evaluation.