Phase separation of RXRγ drives tumor chemoresistance and represents a therapeutic target for small-cell lung cancer
Abstract
Small-cell lung cancer (SCLC) is the most lethal type of lung cancer, characterized by rapid evolution from chemosensitivity to chemoresistance and limited treatment options. However, the mechanisms underlying this evolution remain poorly understood. Here, we show that Retinoid X receptor γ (RXRγ) is uniquely overexpressed in chemo-resistant SCLC tumors, and that RXRγ serves as an essential factor driving chemoresistance in SCLC. RXRγ forms phase-separated droplets with LSD1 in the nucleus, which enhances RXRγ-mediated gene transcription activity and reprograms gene expression, promoting tumor stemness and metastasis, and eventually driving SCLC chemoresistance. In turn, RXRγ antagonist disrupts RXRγ–LSD1 interaction, reducing their binding to the target gene locus, markedly suppressing the expression of the RXRγ target gene network. Finally, RXRγ antagonists strongly suppress tumor growth and metastasis and restore SCLC vulnerability to chemotherapy in multiple preclinical SCLC models, resulting in a substantial extension of survival in mouse models. Thus, these results establish RXRγ as a key player in SCLC by phase separation and as a potential therapeutic target for this deadly disease.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (16)
Hong Wang
Jie Huang
Department of Chemistry
Zhenhua Zhang
Yana An
Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University
Huizi Sun
Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University
Jianghe Chen
Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University
Weineng Feng
Foshan Key Laboratory of Precision Therapy in Oncology and Neurology, Department of Pulmonary Oncology, The First People’s Hospital of Foshan
Hao Duan
Department of Neurosurgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center
Yonggao Mou
Department of Neurosurgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center
Yuanxiang Wang
Balance-Based Drug Discovery Laboratory, School of Pharmaceutical Sciences, Sun Yat-Sen University
Peiqing Liu
National-Local Joint Engineering Lab of Druggability and New Drugs Evaluation, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University
Huihao Zhou
Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University
Hong-Wu Chen
Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis
Jian Zhang
Xiaoyun Lu
School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou 511442, China
Junjian Wang
Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University