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Targeting the SWI/SNF complexes in POU2F transcription factor driven malignancies [ChIP-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: GSE247948 | GEO | 2024/02/15

REPOSITORIES: GEO

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

2024-02-15 | GSE247947 | GEO

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

2024-02-15 | GSE247949 | GEO

Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer [ChIP-Seq]

Project description:This study profiles chromatin accessibility, gene expresison, transcription factor binding, and three-dimensional DNA-DNA contact changes upon rapid SWI/SNF ATPase inactivation in prostate cancer cells. SWI/SNF ATPases activity was disabled using a novel PROTAC degrader compound targeting the SMARCA2, SMARCA4 and PBRM1 subunits of the SWI/SNF remodeling complex.

2021-10-28 | GSE171589 | GEO

Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer [ATAC-Seq]

2021-10-28 | GSE171584 | GEO

Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer [HiChIP-Seq]

2021-10-28 | GSE171591 | GEO

Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer [RNA-Seq]

2021-10-28 | GSE171523 | GEO

Androgen receptor-negative prostate cancer is vulnerable to SWI/SNF-targeting degrader molecules

Project description:The switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex becomes frequently deregulated in advanced castration-resistant prostate cancer (CRPC). SWI/SNF ATPase degrader molecules, also known as Proteolysis targeting chimera (PROTAC), offer a novel approach to tackle resistance to androgen receptor (AR) antagonists in AR-dependent CRPC (CRPC-AR). However, the frequent emergence of AR-negative CRPC remains a major clinical hurdle. We investigated SWI/SNF ATPase targeting agents in AR-negative CRPC. SWI/SNF targeting PROTAC treatment reduced the viability of both CRPC-AR and WNT-signaling dependent CRPC (CRPC-WNT), which accounts for about 10% of all clinical CRPC cases. In CRPC-WNT, we characterized that SWI/SNF ATPase SMARCA4 depletion interfered with WNT signaling via the master transcriptional regulator TCF7L2 (TCF4). Functionally, TCF7L2 maintains proliferation via the AP-1/MAPK signaling axis in this subtype of CRPC.

2024-03-18 | GSE261446 | GEO

Selective PROTAC-mediated degradation and shRNA-driven knockdown of SMARCA2 in HCC2302 lung adenocarcinoma cells

Project description:SMARCA2 and SMARCA4 are mutually-exclusive, core catalytic subunits for the chromatin remodeling SWI/SNF complex. Mutations in SMARCA4 are common in lung adenocarcinoma and have shown synthetic lethality with loss of SMARCA2 loss of function. The purpose of this project is to answer questions related to the in vivo [mouse xenograft] efficacy of A947, a SMARCA2 degrader. The study involves in vitro versus in vivo comparisons of drug activity, in addition to genetic manipulation of the target. Model system: HCC2302 (RRID:CVCL_V636); Model origin: Lung Adenocarcinoma; Perturbation: A947 (VHL-PROTAC-based degrader)

2022-06-13 | GSE205542 | GEO

A SWI/SNF-dependent transcriptional regulation mediated by POU2AF2/C11orf53 at enhancer

Project description:Recent studies have identified a previously uncharacterized protein C11orf53 (now named POU2AF2/OCA-T1), functions as a new co-activator of POU2F3, the master transcription factor which is critical for both normal and neoplastic tuft cell identity and viability. Here, we demonstrated that POU2AF2 functions as an “Yin-Yang” factor which mediates both transcriptional activation and repression at distal enhance elements. Loss of POU2AF2 led to an inhibition of active enhancer nearby genes, such as tuft cell identity genes, and a derepression of Polycomb-dependent poised enhancer nearby genes, which are critical for cell viability and differentiation. Mechanistically, depletion of POU2AF2 leads to a global redistribution of the chromatin occupancy of SWI/SNF complex, resulting in a significant 3D genome structure change and a subsequent transcriptional reprogramming. Genome wide CRISPR screen further demonstrated that POU2AF2 depletion or SWI/SNF inhibition led to a PTEN-dependent cell growth defect, which revealed a potential role of POU2AF2-SWI/SNF axis in small cell lung cancer pathogenesis. Finally, pharmacological inhibition of SWI/SNF phenocopied POU2AF2 depletion in terms of gene expression alteration and cell viability decease in SCLC-P subtype cells. Therefore, impeding POU2AF2 mediated SWI/SNF function represents a potential therapeutic approach for human SCLC therapy.

2024-01-19 | GSE235704 | GEO

Development of an orally bioavailable SWI/SNF ATPase degrader and acquired mechanisms of resistance [WES]

Project description:SWI/SNF ATPase degraders have been shown to be effective in enhancer-driven cancers by functioning to impede oncogenic transcription factor chromatin accessibility. Here we developed AU-24118, a first-in-class, orally bioavailable degrader of SMARCA2/4 and PBRM1. AU-24118 demonstrated tumor regression in a castration resistant model of prostate cancer which was further enhanced in combination with enzalutamide. Prostate cancer cell lines exposed to increasing doses of a SWI/SNF degrader developed SMARCA4 bromodomain mutations and ABCB1 overexpression as acquired mechanisms of resistance. While SMARCA4 mutations provided specific resistance to SWI/SNF degraders, ABCB1 overexpression provided broader resistance to other compounds as well as could be overcome with ABCB1 inhibition.

2024-03-15 | GSE250327 | GEO

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