2025 Hot Topic in Basic & Translational Science: Small Cell Lung Cancer - ePosters-EP01.07: Role of SMARCA4, Core SWI/SNF Complex Component, in Small Cell Lung Cancer Development

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The document pertains to research on Small Cell Lung Cancer (SCLC), emphasizing the role of SMARCA4, a core component of the SWI/SNF chromatin-modifying complex linked to transcription regulation. This study investigates the effects of SMARCA4, which is frequently mutated in SCLC tumors, hypothesizing its function as a tumor suppressor.<br /><br />Despite targeting SMARCA4 with the inhibitor FHD-286 reducing the colony-forming ability of preneoplastic cells and decreasing tumor development in genetically engineered mouse models, deleting SMARCA4 presented unexpected results. The tumors exhibited a variant morphology and lacked neuroendocrine (NE) characteristics, a trait typically observed late in SCLC progression. Strikingly, this transformation coincided with reduced tumor size, contradicting a classical progression pathway, indicating that SMARCA4 might be required for early tumor development, but its loss may promote late-stage malignant transformation.<br /><br />In studies using cells from mature tumors transplanted into mice, knocking down SMARCA4 resulted in accelerated tumor growth, highlighting the temporal specificity of SMARCA4's role in SCLC. This suggests an evolving function of SMARCA4 through different cancer stages, initially supporting tumor development but later enabling transformation after its loss.<br /><br />The research, supported by entities such as the NIH and represented by institutions like the University of Virginia School of Medicine and the National Cancer Institute, reveals crucial insights into the differential impact of chromatin regulation in cancer progression. It supports the notion of context-specific therapeutic targeting of SMARCA4 in SCLC, offering potential pathways for personalized medicine strategies in combating this lethal cancer form.

Asset Subtitle

Nicole Kirk

Keywords

Small Cell Lung Cancer

SCLC

SMARCA4

SWI/SNF complex

tumor suppressor

neuroendocrine characteristics

tumor development

chromatin regulation

personalized medicine

cancer progression