Background/Objectives: Aurora (AK) A/B are oncogenic mitotic kinases that when over-expressed are poor prognostic markers in mantle cell lymphoma (MCL).Methods and Results: Alisertib, an AK-A inhibitor, has anti-tumor activity in relapsed/refractory (r/r) MCL patients. We evaluated alisertib plus ibrutinib in MCL to abrogate ibrutinib resistance. Alisertib plus ibrutinib was therapeutically synergistic on both Granta-519 insensitive to ibrutinib and JeKo-1 cells sensitive to ibrutinib. Alisertib decreased PI-3K, BTK, p38, HCK, and RSK kinases, indicative of its multipotent effect on cellular proliferation and growth. A mouse xenograft model of Granta-519 demonstrated that alisertib plus ibrutinib had a comparable anti-tumor response to ibrutinib plus rituximab. However, alisertib plus ibrutinib plus rituximab demonstrated significantly stronger tumor growth inhibition than the doublets.Conclusions: Both double and triple combinations showed enhanced survival versus ibrutinib alone. Ibrutinib insensitivity can be disrupted by alisertib plus ibrutinib in MCL.
背景/目的：Aurora激酶（AK）A/B是致癌性有丝分裂激酶，其过度表达是套细胞淋巴瘤（MCL）的不良预后标志物。方法与结果：Alisertib作为AK-A抑制剂，在复发/难治性（r/r）MCL患者中展现出抗肿瘤活性。本研究评估aliserib联合依鲁替尼在MCL治疗中逆转依鲁替尼耐药的作用。在依鲁替尼不敏感的Granta-519细胞系和敏感的JeKo-1细胞系中，aliserib与依鲁替尼均显示出协同治疗效应。Aliserib可降低PI-3K、BTK、p38、HCK及RSK激酶活性，表明其对细胞增殖与生长具有多效性抑制作用。Granta-519小鼠异种移植模型实验显示，aliserib联合依鲁替尼的抗肿瘤效果与依鲁替尼联合利妥昔单抗相当。然而，aliserib、依鲁替尼与利妥昔单抗三联方案较双药方案表现出显著更强的肿瘤生长抑制作用。结论：相较于单用依鲁替尼，双联及三联方案均能显著延长生存期。Aliserib联合依鲁替尼可有效克服MCL对依鲁替尼的耐药性。
A Novel Triplet of Alisertib Plus Ibrutinib Plus Rituximab Is Active in Mantle Cell Lymphoma
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