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首页> 外文期刊>Journal of experimental & clinical cancer research : >Small-molecule HDAC and Akt inhibitors suppress tumor growth and enhance immunotherapy in multiple myeloma
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Small-molecule HDAC and Akt inhibitors suppress tumor growth and enhance immunotherapy in multiple myeloma

机译：小分子HDAC和AKT抑制剂抑制肿瘤生长和增强多发性骨髓瘤的免疫疗法

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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. 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. 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. The combination of an HDAC and an Akt inhibitor represents a promising approach for the treatment of relapsed/refractory MM.
机译：多发性骨髓瘤（mm）是一种无法治愈的疾病。获取对药物的耐药性，包括免疫调节药物（IMID）对其预后具有负面影响。遗传（CRBN）是胰岛素等生物活性的关键介质，如Lenalidomide。此外，在耐药患者中经常检测到CRBN的遗传改变，被认为有助于造成耐药性。因此，预期克服对药物的耐药性，包括含有含量的药物，以改善临床结果。在此，我们检查组蛋白脱乙酰化酶（HDAC）抑制剂和AKT抑制剂在复发/难治MM患者中的潜在机制。通过用RNAi介导的下调的下调或使用CRISPR-CAS9在MM细胞中敲除CRBN，我们建立了抗那亚三种致抗性细胞。另外，我们从复发/难治MM患者中衍生多药（Bortezomib，Doxorubicin或地塞米松）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治疗疗效。我们还研究了Lenalidomide对CRBN缺陷细胞的影响。 HDAC抑制剂抑制了耐药MM细胞系的生长，并通过在MM细胞中上调自然杀伤组2D（NKG2D）配体来增强治疗性抗体的抗体依赖性细胞细胞毒性（ADCC）。 CRBN缺陷的细胞显示依赖性胺类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磷酸化来下调C-MYC。 HDAC和AKT抑制剂还表现出协同细胞毒性和C-MYC抑制效果。双HDAC和PI3K抑制剂，CUDC-907，在MM细胞中表现出细胞毒性和免疫疗法增强效果，包括来自Lenalidomide耐药患者的多毒性线和原代细胞。 HDAC和AKT抑制剂的组合代表了用于处理复发/难治性mm的有希望的方法。

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