NFIB Regulates Chemoresistance in Small Cell Lung Cancer by Suppressing Notch Signaling Activity.

[BACKGROUND] Small cell lung cancer (SCLC) is an aggressive malignancy characterized by the rapid development of therapy resistance, the underlying mechanisms of which remain incompletely understood. The transcription factor NFIB is a recognized oncogene in SCLC, promoting tumor progression by regulating metastasis and proliferation. However, its potential role in mediating chemotherapy resistance is poorly defined.

[AIMS] This study aimed to elucidate the mechanism by which NFIB regulates chemoresistance in SCLC and to assess the therapeutic potential of co-targeting NFIB and the Notch signaling pathway.

[METHODS AND RESULTS] Expression of NFIB and associated genes was analyzed in SCLC cell lines and clinical samples using Western blotting, quantitative real-time PCR (qRT-PCR), immunofluorescence (IF), and immunohistochemistry (IHC). Transcriptional regulation was examined by chromatin immunoprecipitation (ChIP), and drug sensitivity was measured via CCK-8 assays. We found that NFIB acts as a dual-function regulator, driving oncogenesis and controlling chemoresistance. NFIB knockdown activated the endogenous Notch pathway, which in turn promoted drug resistance. NFIB expression positively correlated with neuroendocrine (NE) markers and contributed to tumor heterogeneity, a process modulated by Notch1. Mechanistically, loss of NFIB relieved its repression of Notch1, leading to suppressed NE gene expression and yielding slow-cycling, chemoresistant cells with activated Notch signaling. Critically, combining Notch pathway inhibition with chemotherapy attenuated intratumoral heterogeneity and reversed this resistance phenotype.

[CONCLUSIONS] NFIB plays a paradoxical role in SCLC, serving as both an oncogenic driver and a key regulator of chemoresistance via Notch pathway activation. These findings revealed a novel resistance mechanism and propose a promising therapeutic strategy of combined Notch inhibition and chemotherapy for SCLC treatment.