2. Academic Validation
  3. Aberrant JAK-STAT signaling-mediated chromatin remodeling impairs the sensitivity of NK/T-cell lymphoma to chidamide

Aberrant JAK-STAT signaling-mediated chromatin remodeling impairs the sensitivity of NK/T-cell lymphoma to chidamide

  • Clin Epigenetics. 2023 Feb 6;15(1):19. doi: 10.1186/s13148-023-01436-6.
Jinghong Chen # 1,  Zhixiang Zuo # 1,  Yan Gao # 1,  Xiaosai Yao 2,  Peiyong Guan 3,  Yali Wang 1,  Zhimei Li 4,  Zhilong Liu 5,  Jing Han Hong 3,  Peng Deng 1,  Jason Yongsheng Chan 6 7,  Daryl Ming Zhe Cheah 8,  Jingquan Lim 8,  Kelila Xin Ye Chai 8,  Burton Kuan Hui Chia 8,  Jane Wan Lu Pang 8,  Joanna Koh 4,  Dachuan Huang 8,  Haixia He 1,  Yichen Sun 1,  Lizhen Liu 1,  Shini Liu 1,  Yuhua Huang 1,  Xiaoxiao Wang 1,  Hua You 9,  Sahil Ajit Saraf 10,  Nicholas Francis Grigoropoulos 11,  Xiaoqiu Li 12,  Jinxin Bei 1,  Tiebang Kang 1,  Soon Thye Lim 6 8,  Bin Tean Teh 2 3 4 7,  Huiqiang Huang 13,  Choon Kiat Ong 14 15,  Jing Tan 16 17
Affiliations

Affiliations

  • 1 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.
  • 2 Institute of Molecular and Cell Biology, Singapore, Singapore.
  • 3 Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore, Singapore.
  • 4 Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore.
  • 5 Department of Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China.
  • 6 Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
  • 7 Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
  • 8 Lymphoma Genomic Translational Research Laboratory, Cellular and Molecular Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore.
  • 9 Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China.
  • 10 Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore.
  • 11 Department of Hematology, Singapore General Hospital, Singapore, Singapore.
  • 12 Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.
  • 13 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. [email protected].
  • 14 Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore, Singapore. [email protected].
  • 15 Lymphoma Genomic Translational Research Laboratory, Cellular and Molecular Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore. [email protected].
  • 16 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. [email protected].
  • 17 Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore. [email protected].
  • # Contributed equally.
PMID: 36740715 DOI: 10.1186/s13148-023-01436-6
Abstract

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.

Keywords

Chidamide resistance; Chromatin remodeling; HDAC inhibitor; JAK-STAT pathway; NKTL.

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