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Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer.
Xiao, Lanbo; Parolia, Abhijit; Qiao, Yuanyuan; Bawa, Pushpinder; Eyunni, Sanjana; Mannan, Rahul; Carson, Sandra E; Chang, Yu; Wang, Xiaoju; Zhang, Yuping; Vo, Josh N; Kregel, Steven; Simko, Stephanie A; Delekta, Andrew D; Jaber, Mustapha; Zheng, Heng; Apel, Ingrid J; McMurry, Lisa; Su, Fengyun; Wang, Rui; Zelenka-Wang, Sylvia; Sasmal, Sanjita; Khare, Leena; Mukherjee, Subhendu; Abbineni, Chandrasekhar; Aithal, Kiran; Bhakta, Mital S; Ghurye, Jay; Cao, Xuhong; Navone, Nora M; Nesvizhskii, Alexey I; Mehra, Rohit; Vaishampayan, Ulka; Blanchette, Marco; Wang, Yuzhuo; Samajdar, Susanta; Ramachandra, Murali; Chinnaiyan, Arul M.
Affiliation
  • Xiao L; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Parolia A; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Qiao Y; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Bawa P; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Eyunni S; Molecular and Cellular Pathology Program, University of Michigan, Ann Arbor, MI, USA.
  • Mannan R; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Carson SE; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Chang Y; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
  • Wang X; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Zhang Y; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Vo JN; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Kregel S; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Simko SA; Molecular and Cellular Pathology Program, University of Michigan, Ann Arbor, MI, USA.
  • Delekta AD; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Jaber M; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Zheng H; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Apel IJ; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • McMurry L; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Su F; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Wang R; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Zelenka-Wang S; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Sasmal S; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
  • Khare L; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Mukherjee S; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Abbineni C; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Aithal K; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Bhakta MS; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
  • Ghurye J; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Cao X; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Navone NM; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Nesvizhskii AI; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Mehra R; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Vaishampayan U; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Blanchette M; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Wang Y; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Samajdar S; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Ramachandra M; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Chinnaiyan AM; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
Nature ; 601(7893): 434-439, 2022 01.
Article in En | MEDLINE | ID: mdl-34937944
The switch/sucrose non-fermentable (SWI/SNF) complex has a crucial role in chromatin remodelling1 and is altered in over 20% of cancers2,3. Here we developed a proteolysis-targeting chimera (PROTAC) degrader of the SWI/SNF ATPase subunits, SMARCA2 and SMARCA4, called AU-15330. Androgen receptor (AR)+ forkhead box A1 (FOXA1)+ prostate cancer cells are exquisitely sensitive to dual SMARCA2 and SMARCA4 degradation relative to normal and other cancer cell lines. SWI/SNF ATPase degradation rapidly compacts cis-regulatory elements bound by transcription factors that drive prostate cancer cell proliferation, namely AR, FOXA1, ERG and MYC, which dislodges them from chromatin, disables their core enhancer circuitry, and abolishes the downstream oncogenic gene programs. SWI/SNF ATPase degradation also disrupts super-enhancer and promoter looping interactions that wire supra-physiologic expression of the AR, FOXA1 and MYC oncogenes themselves. AU-15330 induces potent inhibition of tumour growth in xenograft models of prostate cancer and synergizes with the AR antagonist enzalutamide, even inducing disease remission in castration-resistant prostate cancer (CRPC) models without toxicity. Thus, impeding SWI/SNF-mediated enhancer accessibility represents a promising therapeutic approach for enhancer-addicted cancers.
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Full text: 1 Database: MEDLINE Main subject: Prostatic Neoplasms / Transcription Factors / Nuclear Proteins / Adenosine Triphosphatases / DNA Helicases Type of study: Prognostic_studies Limits: Animals / Humans / Male Language: En Year: 2022 Type: Article
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Full text: 1 Database: MEDLINE Main subject: Prostatic Neoplasms / Transcription Factors / Nuclear Proteins / Adenosine Triphosphatases / DNA Helicases Type of study: Prognostic_studies Limits: Animals / Humans / Male Language: En Year: 2022 Type: Article