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Targeting the SWI/SNF complexes in POU2F transcription factor driven malignancies [ATAC-seq]

ABSTRACT: The SWI/SNF chromatin-remodeling complex, pivotal in transcriptional regulation, has emerged as a significant player in tumorigenesis, unveiling therapeutic targeting prospects in specific malignancies. This investigation accentuates the potential of targeting the SWI/SNF complex in POU2F3-driven Small Cell Lung Cancer (SCLC) and POU2AF1-dependent multiple myelomas. Employing functional CRISPR screening and pharmacological validation, we identified a distinct and biased dependency of POU2F3-driven SCLC cells on the SWI/SNF complex. In vivo studies exhibited significant tumor growth inhibition in POU2F3-driven SCLC xenografts with an orally administered SMARCA2/4 PROTAC degrader. Furthermore, the exploration extended to POU2AF1 complex-dependent B-cell malignancies, revealing similar sensitivity to the SWI/SNF ATPase PROTAC degrader, suggesting a shared therapeutic potential in POU2F complex-driven malignancies. These collective findings highlight the SWI/SNF complex as a promising therapeutic target, catalyzing the advancement of innovative and efficacious treatment approaches to address these transcription factor-driven malignancies, addressing a critical medical challenge.

ORGANISM(S): Homo sapiens

PROVIDER: GSE247947 | GEO | 2024/02/15

REPOSITORIES: GEO

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Targeting the SWI/SNF complexes in POU2F transcription factor driven malignancies [RNA-seq]

Project description:The SWI/SNF chromatin-remodeling complex, pivotal in transcriptional regulation, has emerged as a significant player in tumorigenesis, unveiling therapeutic targeting prospects in specific malignancies. This investigation accentuates the potential of targeting the SWI/SNF complex in POU2F3-driven Small Cell Lung Cancer (SCLC) and POU2AF1-dependent multiple myelomas. Employing functional CRISPR screening and pharmacological validation, we identified a distinct and biased dependency of POU2F3-driven SCLC cells on the SWI/SNF complex. In vivo studies exhibited significant tumor growth inhibition in POU2F3-driven SCLC xenografts with an orally administered SMARCA2/4 PROTAC degrader. Furthermore, the exploration extended to POU2AF1 complex-dependent B-cell malignancies, revealing similar sensitivity to the SWI/SNF ATPase PROTAC degrader, suggesting a shared therapeutic potential in POU2F complex-driven malignancies. These collective findings highlight the SWI/SNF complex as a promising therapeutic target, catalyzing the advancement of innovative and efficacious treatment approaches to address these transcription factor-driven malignancies, addressing a critical medical challenge.

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Mammalian SWI/SNF complex activity regulates POU2F3 and constitutes a targetable dependency in small cell lung cancer

Project description:Small cell lung cancers (SCLC) are comprised of heterogeneous subtypes marked by lineage-specific transcription factors, including ASCL1, NEUROD1, and POU2F3. POU2F3-positive SCLC, ~12% of all cases, are uniquely dependent on POU2F3 itself; as such, approaches to attenuate POU2F3 expression may represent new therapeutic opportunities for this subtype. Here using genome-scale CRISPR/Cas9-based screens reporting on POU2F3 expression in SCLC cell lines, we define mSWI/SNF complexes, including non-canonical BAF complexes (ncBAF), as top regulators of POU2F3 and dependencies specific to the POU2F3-positive subtype. Notably, clinical-grade pharmacologic mSWI/SNF complex inhibition attenuates proliferation of all POU2F3-positive SCLCs, while disruption of ncBAF via BRD9 degradation is uniquely effective in pure non-neuroendocrine POU2F3-SCLCs. mSWI/SNF complexes maintain accessibility over gene loci central to POU2F3-mediated gene regulatory networks. Finally, chemical targeting of SMARCA4/2 mSWI/SNF ATPases and BRD9 decrease POU2F3-SCLC tumor growth and increase survival in vivo. Taken together, these results define mSWI/SNF-mediated global governance of the POU2F3 oncogenic program and suggest mSWI/SNF inhibition as a therapeutic strategy in SCLC.

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Non-Canonical BAF and mSWI/SNF Regulates POU2F3 and are Selective Targetable Dependencies for POU2F3-Positive Small Cell Lung Cancer

Project description:~12% of SCLCs are marked by the lineage transcription factor POU2F3, which is essential in all POU2F3-positive SCLCs. Thus, approaches to directly or indirectly inhibit POU2F3 could lead to new therapeutic strategies for POU2F3-positive SCLCs. Here we use a positive selection screening strategy where endogenous POU2F3 is fused to the suicide gene DCK*. Cells that express endogenous POU2F3-DCK* are killed in the presence of the nucleoside analog BVdU and only cells that downregulate the POU2F3-DCK* fusion survive. Genome-wide CRISPR/Cas9 resistance screens with BVdU in POU2F3-DCK* cells uncovered that inactivation of SMARCD1 or BRD9, both components of the non-canonical BAF (ncBAF) complex, markedly downregulate endogenous POU2F3. We find that all POU2F3-positive SCLC cell lines relative to ASCL1-positive and NEUROD1-positive cell lines, are exquisitely sensitive to mSWI/SNF complex inhibition using SMARCA2/4 inhibitors; while pure non-neuroendocrine POU2F3-positive SCLC cell lines are highly sensitive to ncBAF complex inhibition using highly selective BRD9 degraders. Mechanistically, BRD9 binds and regulates POU2F3 target genes including POU2F3 itself. BRD9 degraders or SMARCA2/4 inhibitors robustly decrease accessibility of POU2F3 target genes effectively shutting off POU2F3 function. Moreover, BRD9 degraders or SMARCA2/4 inhibitors decrease tumor growth and increase survival of mice bearing non-neuroendocrine POU2F3 xenografts. This works shows that mSWI/SNF and ncBAF tightly regulate POU2F3 expression and activity and nominate mSWI/SNF or ncBAF inhibition as druggable therapeutic strategies to selectively target POU2F3-positive SCLCs.

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