小分子 HDAC 和 Akt 抑制剂抑制多发性骨髓瘤的肿瘤生长并增强免疫治疗。
Small-molecule HDAC and Akt inhibitors suppress tumor growth and enhance immunotherapy in multiple myeloma.
机构信息
Division of Molecular Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Department of Hematology/Oncology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
出版信息
J Exp Clin Cancer Res. 2021 Mar 23;40(1):110. doi: 10.1186/s13046-021-01909-7.
BACKGROUND
Multiple myeloma (MM) is an incurable disease. The acquisition of resistance to drugs, including immunomodulatory drugs (IMiDs), has a negative effect on its prognosis. Cereblon (CRBN) is a key mediator of the bioactivities of IMiDs such as lenalidomide. Moreover, genetic alteration of CRBN is frequently detected in IMiD-resistant patients and is considered to contribute to IMiD resistance. Thus, overcoming resistance to drugs, including IMiDs, is expected to improve clinical outcomes. Here, we examined potential mechanisms of a histone deacetylase (HDAC) inhibitor and Akt inhibitor in relapsed/refractory MM patients.
METHODS
We established lenalidomide-resistant cells by knocking down CRBN with RNAi-mediated downregulation or knocking out CRBN using CRISPR-Cas9 in MM cells. Additionally, we derived multi-drug (bortezomib, doxorubicin, or dexamethasone)-resistant cell lines and primary cells from relapsed/refractory MM patients. The effects of HDAC and Akt inhibitors on these drug-resistant MM cells were then observed with a particular focus on whether HDAC inhibitors enhance immunotherapy efficacy. We also investigated the effect of lenalidomide on CRBN-deficient cells.
RESULTS
The HDAC inhibitor suppressed the growth of drug-resistant MM cell lines and enhanced the antibody-dependent cellular cytotoxicity (ADCC) of therapeutic antibodies by upregulating natural killer group 2D (NKG2D) ligands in MM cells. CRBN-deficient cells showed lenalidomide-induced upregulation of phosphorylated glycogen synthase kinase-3 (p-GSK-3) and c-Myc phosphorylation. Moreover, HDAC and Akt inhibitors downregulated c-Myc by blocking GSK-3 phosphorylation. HDAC and Akt inhibitors also exhibited synergistic cytotoxic and c-Myc-suppressive effects. The dual HDAC and PI3K inhibitor, CUDC-907, exhibited cytotoxic and immunotherapy-enhancing effects in MM cells, including multi-drug-resistant lines and primary cells from lenalidomide-resistant patients.
CONCLUSIONS
The combination of an HDAC and an Akt inhibitor represents a promising approach for the treatment of relapsed/refractory MM.
背景
多发性骨髓瘤（MM）是一种无法治愈的疾病。对药物（包括免疫调节剂（IMiDs））的耐药性的获得对其预后产生负面影响。 cereblon（CRBN）是 lenalidomide 等 IMiD 生物活性的关键介质。此外，在 IMiD 耐药患者中经常检测到 CRBN 的遗传改变，并且认为其有助于 IMiD 耐药。因此，克服包括 IMiD 在内的药物耐药性有望改善临床结局。在这里，我们研究了组蛋白去乙酰化酶（HDAC）抑制剂和 Akt 抑制剂在复发性/难治性 MM 患者中的潜在机制。
方法
我们通过使用 RNAi 介导的下调或使用 CRISPR-Cas9 敲除 MM 细胞中的 CRBN 来建立 lenalidomide 耐药细胞。此外，我们从复发性/难治性 MM 患者中衍生出多药（硼替佐米，阿霉素或地塞米松）耐药细胞系和原代细胞。然后观察 HDAC 和 Akt 抑制剂对这些耐药 MM 细胞的影响，特别关注 HDAC 抑制剂是否增强免疫疗法的功效。我们还研究了 lenalidomide 对 CRBN 缺陷细胞的影响。
结果
HDAC 抑制剂抑制了耐药 MM 细胞系的生长，并通过上调 MM 细胞中自然杀伤组 2D（NKG2D）配体增强了治疗性抗体的抗体依赖性细胞毒性（ADCC）。CRBN 缺陷细胞表现出 lenalidomide 诱导的磷酸化糖原合酶激酶-3（p-GSK-3）和 c-Myc 磷酸化的上调。此外，HDAC 和 Akt 抑制剂通过阻断 GSK-3 磷酸化而下调 c-Myc。HDAC 和 Akt 抑制剂还表现出协同的细胞毒性和 c-Myc 抑制作用。双重 HDAC 和 PI3K 抑制剂 CUDC-907 在 MM 细胞中具有细胞毒性和免疫治疗增强作用，包括多药耐药株和来自 lenalidomide 耐药患者的原代细胞。
结论
HDAC 和 Akt 抑制剂的联合使用为治疗复发性/难治性 MM 提供了一种有前途的方法。
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