Phase separation of RXRγ drives tumor chemoresistance and represents a therapeutic target for small-cell lung cancer

• 成果类型: Article
• 署名作者: Wang, Hong; Huang, Jie; Zhang, Zhenhua; An, Yana; Sun, Huizi; Chen, Jianghe; Feng, Weineng; Duan, Hao; Mou, Yonggao; Wang, Yuanxiang; Liu, Peiqing; Zhou, Huihao; Chen, Hong - Wu; Zhang, Jian; Lu, Xiaoyun; Wang, Junjian
• 署名单位: Sun Yat Sen University; Guangdong Academy of Medical Sciences & Guangdong General Hospital; Southern Medical University - China; Sun Yat Sen University; State Key Lab Oncology South China; Sun Yat Sen University; University of California System; University of California Davis; Sun Yat Sen University; Jinan University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8971
• DOI: 10.1073/pnas.2421199122
• 发表日期: 2025-05-20
• 关键词: lsd1; receptors; resistance

摘要

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 gamma (RXR gamma) is uniquely overexpressed in chemo-resistant SCLC tumors, and that RXR gamma serves as an essential factor driving chemoresistance in SCLC. RXR gamma forms phase-separated droplets with LSD1 in the nucleus, which enhances RXR gamma- mediated gene transcription activity and reprograms gene expression, promoting tumor stemness and metastasis, and eventually driving SCLC chemoresistance. In turn, RXR gamma antagonist disrupts RXR gamma-LSD1 interaction, reducing their binding to the target gene locus, markedly suppressing the expression of the RXR gamma target gene network. Finally, RXR gamma 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 RXR gamma as a key player in SCLC by phase separation and as a potential therapeutic target for this deadly disease.