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
Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, China.
Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China.
Proc Natl Acad Sci U S A. 2025 May 27;122(21):e2421199122. doi: 10.1073/pnas.2421199122. Epub 2025 May 20.
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.
小细胞肺癌（SCLC）是最致命的肺癌类型，其特点是从化疗敏感性迅速演变为化疗耐药性，且治疗选择有限。然而，这种演变背后的机制仍知之甚少。在此，我们表明视黄酸X受体γ（RXRγ）在化疗耐药的SCLC肿瘤中独特地过度表达，并且RXRγ是驱动SCLC化疗耐药的关键因素。RXRγ在细胞核中与赖氨酸特异性去甲基化酶1（LSD1）形成相分离的液滴，这增强了RXRγ介导的基因转录活性并重新编程基因表达，促进肿瘤干性和转移，最终导致SCLC化疗耐药。反过来，RXRγ拮抗剂破坏RXRγ-LSD1相互作用，减少它们与靶基因位点的结合，显著抑制RXRγ靶基因网络的表达。最后，在多个临床前SCLC模型中，RXRγ拮抗剂强烈抑制肿瘤生长和转移，并恢复SCLC对化疗的敏感性，从而显著延长小鼠模型的生存期。因此，这些结果确立了RXRγ通过相分离在SCLC中作为关键角色以及作为这种致命疾病潜在治疗靶点的地位。
