Abstract
Our study elucidates the role of FOXP1 in chemoresistance in small cell lung cancer(SCLC). FOXP1 enhances chemoresistance by regulating SP8 expression through its super-enhancer (SP8-SE), with SP8 mediating resistance via the homologous recombination repair (HRR) pathway. We also discovered that FOXP1 forms punctate nuclear structures indicative of liquid-liquid phase separation, crucial for its transcriptional regulation. Targeting the FOXP1-SP8-HR axis with BRD4 and PARP inhibitors showed synergistic effects in reducing tumor growth in vitro and in patient-derived xenograft models. These findings identify FOXP1 as a critical mediator and marker of chemoresistance in SCLC, providing a foundation for developing targeted therapies to overcome this resistance.
© 2025. The Author(s).
MeSH terms
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Animals
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Bromodomain Containing Proteins
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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Drug Resistance, Neoplasm* / genetics
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Forkhead Transcription Factors* / genetics
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Forkhead Transcription Factors* / metabolism
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Lung Neoplasms* / drug therapy
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Lung Neoplasms* / genetics
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Lung Neoplasms* / metabolism
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Lung Neoplasms* / pathology
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Mice
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Phase Separation
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Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
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Repressor Proteins* / genetics
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Repressor Proteins* / metabolism
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Small Cell Lung Carcinoma* / drug therapy
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Small Cell Lung Carcinoma* / genetics
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Small Cell Lung Carcinoma* / metabolism
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Small Cell Lung Carcinoma* / pathology
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Xenograft Model Antitumor Assays
Substances
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Forkhead Transcription Factors
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FOXP1 protein, human
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Repressor Proteins
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Transcription Factors
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Cell Cycle Proteins
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BRD4 protein, human
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Poly(ADP-ribose) Polymerase Inhibitors
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Bromodomain Containing Proteins