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.
J Exp Clin Cancer Res. 2021 Mar 23;40(1):110. doi: 10.1186/s13046-021-01909-7.
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.
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。
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。
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。
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。
