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

Small cell lung cancer (SCLC) is the most lethal type of lung cancer, characterized by limited treatment options and rapid evolution from chemosensitivity to chemoresistance. However, the mechanisms underlying this evolution remain poorly understood. Identifying the druggable drivers and developing pharmacological strategies to overcome chemoresistance are imperative. Here, we show that Retinoid X receptor ? (RXR?) is uniquely overexpressed in chemo-resistant SCLC tumors, and that RXR? serves as an essential factor driving chemoresistance in SCLC. RXR? forms phase-separated droplets with LSD1 in the nucleus, which enhances RXR?-mediated gene transcription activity and reprograms gene expression, promoting tumor stemness and metastasis, and eventually driving SCLC chemoresistance. In turn, RXR? antagonist disrupts RXR?-LSD1 interaction, reducing their binding to the target gene locus, markedly suppressing the expression of the RXR? target gene network. Finally, RXR? antagonists strongly suppress tumor growth and metastasis and restore SCLC vulnerability to chemotherapy in multiple preclinical SCLC models, without overt toxicity, in mice. Thus, these results establish RXR? as a key player in SCLC by phase separation and as a potential therapeutic target for this deadly disease. Overall design: H128 cells were treated with HX531 for 48 h. (Control group, we named Con-2; treated group, we named H10-2)