异常的 JAK-STAT 信号转导介导的染色质重塑会损害 NK/T 细胞淋巴瘤对沙利度胺的敏感性。
Aberrant JAK-STAT signaling-mediated chromatin remodeling impairs the sensitivity of NK/T-cell lymphoma to chidamide.
机构信息
State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University Cancer Center, 651 East Dongfeng Road, Guangzhou, 510060, China.
Institute of Molecular and Cell Biology, Singapore, Singapore.
出版信息
Clin Epigenetics. 2023 Feb 6;15(1):19. doi: 10.1186/s13148-023-01436-6.
BACKGROUND
Natural killer/T-cell lymphoma (NKTL) is a rare type of aggressive and heterogeneous non-Hodgkin's lymphoma (NHL) with a poor prognosis and limited therapeutic options. Therefore, there is an urgent need to exploit potential novel therapeutic targets for the treatment of NKTL. Histone deacetylase (HDAC) inhibitor chidamide was recently approved for treating relapsed/refractory peripheral T-cell lymphoma (PTCL) patients. However, its therapeutic efficacy in NKTL remains unclear.
METHODS
We performed a phase II clinical trial to evaluate the efficacy of chidamide in 28 relapsed/refractory NKTL patients. Integrative transcriptomic, chromatin profiling analysis and functional studies were performed to identify potential predictive biomarkers and unravel the mechanisms of resistance to chidamide. Immunohistochemistry (IHC) was used to validate the predictive biomarkers in tumors from the clinical trial.
RESULTS
We demonstrated that chidamide is effective in treating relapsed/refractory NKTL patients, achieving an overall response and complete response rate of 39 and 18%, respectively. In vitro studies showed that hyperactivity of JAK-STAT signaling in NKTL cell lines was associated with the resistance to chidamide. Mechanistically, our results revealed that aberrant JAK-STAT signaling remodels the chromatin and confers resistance to chidamide. Subsequently, inhibition of JAK-STAT activity could overcome resistance to chidamide by reprogramming the chromatin from a resistant to sensitive state, leading to synergistic anti-tumor effect in vitro and in vivo. More importantly, our clinical data demonstrated that combinatorial therapy with chidamide and JAK inhibitor ruxolitinib is effective against chidamide-resistant NKTL. In addition, we identified TNFRSF8 (CD30), a downstream target of the JAK-STAT pathway, as a potential biomarker that could predict NKTL sensitivity to chidamide.
CONCLUSIONS
Our study suggests that chidamide, in combination with JAK-STAT inhibitors, can be a novel targeted therapy in the standard of care for NKTL.
TRIAL REGISTRATION
ClinicalTrials.gov, NCT02878278. Registered 25 August 2016, https://clinicaltrials.gov/ct2/show/NCT02878278.
背景
自然杀伤/T 细胞淋巴瘤（NKTL）是一种罕见的侵袭性和异质性非霍奇金淋巴瘤（NHL），预后差，治疗选择有限。因此，迫切需要寻找治疗 NKTL 的潜在新治疗靶点。组蛋白去乙酰化酶（HDAC）抑制剂西达本胺最近被批准用于治疗复发/难治性外周 T 细胞淋巴瘤（PTCL）患者。然而，其在 NKTL 中的治疗效果尚不清楚。
方法
我们进行了一项 II 期临床试验，以评估西达本胺在 28 例复发/难治性 NKTL 患者中的疗效。进行了综合转录组学、染色质谱分析和功能研究，以鉴定潜在的预测生物标志物，并揭示对西达本胺耐药的机制。免疫组织化学（IHC）用于验证临床试验中肿瘤的预测生物标志物。
结果
我们证明西达本胺在治疗复发/难治性 NKTL 患者中是有效的，总缓解率和完全缓解率分别为 39%和 18%。体外研究表明，NKTL 细胞系中 JAK-STAT 信号的过度活跃与对西达本胺的耐药性有关。机制上，我们的结果表明，异常的 JAK-STAT 信号重塑染色质，赋予对西达本胺的耐药性。随后，通过将耐药状态的染色质从耐药状态重编程为敏感状态，抑制 JAK-STAT 活性可以克服对西达本胺的耐药性，从而在体外和体内产生协同的抗肿瘤作用。更重要的是，我们的临床数据表明，西达本胺与 JAK 抑制剂芦可替尼联合治疗对西达本胺耐药的 NKTL 有效。此外，我们鉴定了 TNFRSF8（CD30），JAK-STAT 通路的下游靶点，作为预测 NKTL 对西达本胺敏感性的潜在生物标志物。
结论
我们的研究表明，西达本胺联合 JAK-STAT 抑制剂可能成为 NKTL 标准治疗中的一种新的靶向治疗方法。
试验注册
ClinicalTrials.gov，NCT02878278。于 2016 年 8 月 25 日注册，https://clinicaltrials.gov/ct2/show/NCT02878278。
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