Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer
Author:
Xiao Lanbo, Parolia Abhijit, Qiao YuanyuanORCID, Bawa PushpinderORCID, Eyunni Sanjana, Mannan RahulORCID, Carson Sandra E.ORCID, 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 LeenaORCID, Mukherjee Subhendu, Abbineni Chandrasekhar, Aithal Kiran, Bhakta Mital S., Ghurye Jay, Cao Xuhong, Navone Nora M.ORCID, Nesvizhskii Alexey I.ORCID, Mehra RohitORCID, Vaishampayan Ulka, Blanchette Marco, Wang YuzhuoORCID, Samajdar Susanta, Ramachandra Murali, Chinnaiyan Arul M.ORCID
Abstract
AbstractThe 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.
Publisher
Springer Science and Business Media LLC
Subject
Multidisciplinary
Reference47 articles.
1. Kassabov, S. R., Zhang, B., Persinger, J. & Bartholomew, B. SWI/SNF unwraps, slides, and rewraps the nucleosome. Mol. Cell 11, 391–403 (2003). 2. Kadoch, C. et al. Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nat. Genet. 45, 592–601 (2013). 3. Shain, A. H. & Pollack, J. R. The spectrum of SWI/SNF mutations, ubiquitous in human cancers. PLoS ONE 8, e55119 (2013). 4. Bednar, J. et al. Nucleosomes, linker DNA, and linker histone form a unique structural motif that directs the higher-order folding and compaction of chromatin. Proc. Natl. Acad. Sci. USA 95, 14173–14178 (1998). 5. Adelman, K. & Lis, J. T. How does Pol II overcome the nucleosome barrier? Mol. Cell 9, 451–452 (2002).
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