Upregulation of CD38 expression on multiple myeloma cells by novel HDAC6 inhibitors is a class effect and augments the efficacy of daratumumab.
Upregulation of CD38 expression on multiple myeloma cells by novel HDAC6 inhibitors is a class effect and augments the efficacy of daratumumab.
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DOI：
10.1038/s41375-020-0840-y
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发表时间：
2021-01
期刊：
影响因子：
11.4
通讯作者：
Danhof S
中科院分区：
文献类型：
--
作者：
García-Guerrero E;Götz R;Doose S;Sauer M;Rodríguez-Gil A;Nerreter T;Kortüm KM;Pérez-Simón JA;Einsele H;Hudecek M;Danhof S
多发性骨髓瘤（MM）是无法治愈的，因此对复发性或难治性疾病患者的有效治疗存在显著未满足的需求。尽管抗CD 38抗体达雷妥尤单抗（MM治疗中最有效的药物之一）最近获得批准，但这种情况并未改变。达雷妥尤单抗与协同抗MM药物联合使用可提高疗效。因此，我们研究了组蛋白去乙酰化酶（HDAC）抑制剂ricolinostat上调MM细胞上CD 38的潜力，从而增强CD 38特异性治疗的性能。使用定量逆转录聚合酶链反应和流式细胞术，我们观察到ricolinostat显著增加MM细胞上的CD 38 RNA水平和CD 38表面表达。通过直接随机光学重建显微镜对MM细胞进行的超分辨率显微镜成像证实了这种分子分辨率的上升，并揭示了CD 38分子在细胞膜上的均匀分布。特别重要的是，ricolinostat与daratumumab组合诱导MM细胞裂解增强。我们还评估了下一代HDAC 6抑制剂（ACY-241，WT-161），并观察到CD 38水平的相似增加，表明HDAC 6抑制剂上调MM细胞上的CD 38表达是一类效应。这一概念验证说明了HDAC 6抑制剂和CD 38定向免疫疗法联合治疗MM的潜在获益。
Multiple myeloma (MM) is incurable, so there is a significant unmet need for effective therapy for patients with relapsed or refractory disease. This situation has not changed despite the recent approval of the anti-CD38 antibody daratumumab, one of the most potent agents in MM treatment. The efficiency of daratumumab might be improved by combining it with synergistic anti-MM agents. We therefore investigated the potential of the histone deacetylase (HDAC) inhibitor ricolinostat to up-regulate CD38 on MM cells, thereby enhancing the performance of CD38-specific therapies. Using quantitative reverse transcription polymerase chain reaction and flow cytometry, we observed that ricolinostat significantly increases CD38 RNA levels and CD38 surface expression on MM cells. Super-resolution microscopy imaging of MM cells by direct stochastic optical reconstruction microscopy confirmed this rise with molecular resolution and revealed homogeneous distribution of CD38 molecules on the cell membrane. Particularly important is that combining ricolinostat with daratumumab induced enhanced lysis of MM cells. We also evaluated next-generation HDAC6 inhibitors (ACY-241, WT-161) and observed similar increase of CD38 levels suggesting that the upregulation of CD38 expression on MM cells by HDAC6 inhibitors is a class effect. This proof-of-concept illustrates the potential benefit of combining HDAC6 inhibitors and CD38-directed immunotherapy for MM treatment.
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影响因子：
11.4
作者：
Kumar SK;Lee JH;Lahuerta JJ;Morgan G;Richardson PG;Crowley J;Haessler J;Feather J;Hoering A;Moreau P;LeLeu X;Hulin C;Klein SK;Sonneveld P;Siegel D;Bladé J;Goldschmidt H;Jagannath S;Miguel JS;Orlowski R;Palumbo A;Sezer O;Rajkumar SV;Durie BG;International Myeloma Working Group
通讯作者：
International Myeloma Working Group
影响因子：
158.5
作者：
Lonial, Sagar;Dimopoulos, Meletios;Richardson, Paul
通讯作者：
Richardson, Paul
DOI：
10.1007/s00262-018-2140-1
发表时间：
2018-06
期刊：
Cancer immunology, immunotherapy : CII
影响因子：
--
作者：
Mahaweni NM;Bos GMJ;Mitsiades CS;Tilanus MGJ;Wieten L
通讯作者：
Wieten L
影响因子：
56.9
作者：
HOWARD, M;GRIMALDI, JC;LEE, HC
通讯作者：
LEE, HC
DOI：
10.1158/1078-0432.ccr-12-2422
发表时间：
2013-04-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Carpenter RO;Evbuomwan MO;Pittaluga S;Rose JJ;Raffeld M;Yang S;Gress RE;Hakim FT;Kochenderfer JN
通讯作者：
Kochenderfer JN