Department of Hematology, Huadong Hospital, Fudan University, Shanghai 200040, China; Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai 200040, China.
Department of Hematology, Huadong Hospital, Fudan University, Shanghai 200040, China.
EBioMedicine. 2017 Jun;20:70-78. doi: 10.1016/j.ebiom.2017.04.037. Epub 2017 May 10.
At our center, relapsed mantle cell lymphoma (MCL) can be treated with maintenance therapy composed of consecutive low-dose lenalidomide and short-term, high-dose dexamethasone (LD regimen), which achieves good responses (longer overall survival and progression-free survival) and low toxicity. Cereblon is probably targeted by both lenalidomide and dexamethasone, which leads to synergistic cytotoxicity in MCL by inhibiting the interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3), phosphatidylinositol 3-kinase (PI3K)/AKT and AKT2/Forkhead box O3 (FOXO3A)/BCL2-like 11 (BIM) pathways. The two drugs synergistically inhibit the same pathways, but through different sites. Cereblon was found expressed in most of the MCL tissues (91.3% positivity). Moreover, cereblon expression is positively correlated with LD regimen sensitivity: long-term lenalidomide exposure downregulates cereblon and induces multi-drug resistance against lenalidomide, dexamethasone, cytarabine, cisplatin, and methotrexate in vitro. Removal of lenalidomide resensitizes lenalidomide-resistant MCL cells to lenalidomide and dexamethasone. Our work suggests that rotating the LD regimen with other regimens would improve MCL maintenance therapy.
在我们中心，复发的套细胞淋巴瘤（MCL）可以用连续低剂量来那度胺和短期高剂量地塞米松组成的维持治疗（LD 方案）来治疗，该方案可取得良好的反应（更长的总生存期和无进展生存期）和低毒性。来那度胺和地塞米松可能靶向 cereblon，通过抑制白细胞介素 6/信号转导和转录激活因子 3（IL-6/STAT3）、磷脂酰肌醇 3-激酶（PI3K）/蛋白激酶 B（AKT）和 AKT2/叉头框 O3（FOXO3A）/B 淋巴细胞瘤-2 样 11（BIM）通路，导致 MCL 的协同细胞毒性。这两种药物通过不同的位点协同抑制相同的通路。在大多数 MCL 组织中发现 cereblon 表达（91.3%阳性）。此外，cereblon 的表达与 LD 方案的敏感性呈正相关：长期来那度胺暴露下调 cereblon，并在体外诱导对来那度胺、地塞米松、阿糖胞苷、顺铂和甲氨蝶呤的多药耐药。去除来那度胺可使来那度胺耐药的 MCL 细胞对来那度胺和地塞米松重新敏感。我们的工作表明，用其他方案轮换 LD 方案将改善 MCL 的维持治疗。
