Androgen receptor-negative prostate cancer is vulnerable to SWI/SNF-targeting degrader molecules
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ABSTRACT:
PROVIDER: PRJNA1086957 | ENA |
REPOSITORIES: ENA
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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
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
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 | GSE250326 | GEO
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 | GSE171591 | GEO
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
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 | GSE171584 | GEO
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 | GSE171523 | GEO
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 | GSE247949 | GEO
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 | GSE247948 | GEO
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