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

Feb 06, 2023

Contributors: Jinghong Chen,Zhixiang Zuo,Yan Gao,Xiaosai Yao,Peiyong Guan,Yali Wang,Zhimei Li,Zhilong Liu,Jing Han Hong,Peng Deng,Jason Yongsheng Chan,Daryl Ming Zhe Cheah,Jingquan Lim,Kelila Xin Ye Chai,Burton Kuan Hui Chia,Jane Wan Lu Pang,Joanna Koh,Dachuan Huang,Haixia He,Yichen Sun,Lizhen Liu,Shini Liu,Yuhua Huang,Xiaoxiao Wang,Hua You,Sahil Ajit Saraf,Nicholas Francis Grigoropoulos,Xiaoqiu Li,Jinxin Bei,Tiebang Kang,Soon Thye Lim,Bin Tean Teh,Huiqiang Huang,Choon Kiat Ong,Jing Tan

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.
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.
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.
Our study suggests that chidamide, in combination with JAK-STAT inhibitors, can be a novel targeted therapy in the standard of care for NKTL.
ClinicalTrials.gov, NCT02878278. Registered 25 August 2016, https://clinicaltrials.gov/ct2/show/NCT02878278.

© 2023. The Author(s).

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ABOUT THE CONTRIBUTORS

Jinghong Chen,Zhixiang Zuo,Yan Gao,Xiaosai Yao,Peiyong Guan,Yali Wang,Zhimei Li,Zhilong Liu,Jing Han Hong,Peng Deng,Jason Yongsheng Chan,Daryl Ming Zhe Cheah,Jingquan Lim,Kelila Xin Ye Chai,Burton Kuan Hui Chia,Jane Wan Lu Pang,Joanna Koh,Dachuan Huang,Haixia He,Yichen Sun,Lizhen Liu,Shini Liu,Yuhua Huang,Xiaoxiao Wang,Hua You,Sahil Ajit Saraf,Nicholas Francis Grigoropoulos,Xiaoqiu Li,Jinxin Bei,Tiebang Kang,Soon Thye Lim,Bin Tean Teh,Huiqiang Huang,Choon Kiat Ong,Jing Tan
Jinghong Chen

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.

Zhixiang Zuo

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.

Yan Gao

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.

Xiaosai Yao

Institute of Molecular and Cell Biology, Singapore, Singapore.

Peiyong Guan

Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore, Singapore.

Yali Wang

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.

Zhimei Li

Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore.

Zhilong Liu

Department of Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China.

Jing Han Hong

Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore, Singapore.

Peng Deng

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.

Jason Yongsheng Chan

Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.

Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.

Daryl Ming Zhe Cheah

Lymphoma Genomic Translational Research Laboratory, Cellular and Molecular Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore.

Jingquan Lim

Lymphoma Genomic Translational Research Laboratory, Cellular and Molecular Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore.

Kelila Xin Ye Chai

Lymphoma Genomic Translational Research Laboratory, Cellular and Molecular Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore.

Burton Kuan Hui Chia

Lymphoma Genomic Translational Research Laboratory, Cellular and Molecular Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore.

Jane Wan Lu Pang

Lymphoma Genomic Translational Research Laboratory, Cellular and Molecular Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore.

Joanna Koh

Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore.

Dachuan Huang

Lymphoma Genomic Translational Research Laboratory, Cellular and Molecular Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore.

Haixia He

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.

Yichen Sun

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.

Lizhen Liu

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.

Shini Liu

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.

Yuhua Huang

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.

Xiaoxiao Wang

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.

Hua You

Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China.

Sahil Ajit Saraf

Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore.

Nicholas Francis Grigoropoulos

Department of Hematology, Singapore General Hospital, Singapore, Singapore.

Xiaoqiu Li

Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.

Jinxin Bei

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.

Tiebang Kang

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.

Soon Thye Lim

Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.

Lymphoma Genomic Translational Research Laboratory, Cellular and Molecular Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore.

Bin Tean Teh

Institute of Molecular and Cell Biology, Singapore, Singapore.

Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore, Singapore.

Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore.

Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.

Huiqiang Huang

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. huanghq@sysucc.org.cn.

Choon Kiat Ong

Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore, Singapore. gmsock@nus.edu.sg.

Lymphoma Genomic Translational Research Laboratory, Cellular and Molecular Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore. gmsock@nus.edu.sg.

Jing Tan

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. tanjing@sysucc.org.cn.

Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore. tanjing@sysucc.org.cn.