Department of Dermatology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan; Division of Rare Cancer Research, National Cancer Center Research Institute, Tokyo, Japan.
Department of Dermatology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan; Division of Rare Cancer Research, National Cancer Center Research Institute, Tokyo, Japan.
J Dermatol Sci. 2021 Mar;101(3):194-201. doi: 10.1016/j.jdermsci.2021.01.004. Epub 2021 Jan 22.
Histone deacetylase inhibitors (HDACi) are used to treat patients with cutaneous T-cell lymphoma (CTCL), but they show limited efficacy. Hence, combination therapies should be explored to enhance the effectiveness of HDACis.
This study was conducted to identify novel therapeutic targets that can be combined with HDACis for treating CTCL.
We performed a global kinome profiling assay of three CTCL cell lines (HH, MJ, and Hut78) with three HDACis (romidepsin, vorinostat, and belinostat) using the PamChip® microarray. The three cell lines were co-treated with romidepsin and an inhibitor against the tyrosine kinase pathway.
Principal component analysis revealed that kinome expression patterns were mainly related to the cell origin and were not affected by the drugs. Few kinases were commonly activated by the HDACis. Most identified kinases were Src-associated molecules, such as annexin A2, embryonal Fyn-associated substrate, and progesterone receptor. Phosphorylated Src was not observed in any untreated cell lines, whereas Src phosphorylation was detected in two of the three cell lines after HDACi treatment. Ponatinib, a Src inhibitor, significantly enhanced romidepsin-induced apoptosis not only in HH, MJ, and Hut78 cells, but also in Myla and SeAx CTCL cell lines.
The Src pathway is a possible target for combination therapy involving HDACis for CTCL.
组蛋白去乙酰化酶抑制剂（HDACi）被用于治疗皮肤 T 细胞淋巴瘤（CTCL）患者，但疗效有限。因此，应探索联合治疗方法以增强 HDACi 的效果。
本研究旨在确定可与 HDACi 联合用于治疗 CTCL 的新型治疗靶点。
我们使用 PamChip®微阵列对三种 CTCL 细胞系（HH、MJ 和 Hut78）进行了三种 HDACi（罗米地辛、伏立诺他和贝林司他）的全激酶组谱分析。将这三种细胞系与罗米地辛和一种针对酪氨酸激酶途径的抑制剂共同处理。
主成分分析显示，激酶组表达模式主要与细胞起源有关，不受药物影响。很少有激酶被 HDACi 共同激活。大多数鉴定出的激酶都是Src 相关分子，如膜联蛋白 A2、胚胎 Fyn 相关底物和孕激素受体。未处理的细胞系中均未观察到磷酸化 Src，而在三种细胞系中的两种经 HDACi 处理后检测到 Src 磷酸化。Src 抑制剂 ponatinib 不仅在 HH、MJ 和 Hut78 细胞中，而且在 Myla 和 SeAx CTCL 细胞系中，均显著增强了 romidepsin 诱导的细胞凋亡。
Src 途径可能是涉及 CTCL 的 HDACi 联合治疗的潜在靶点。
