Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer

Lanbo Xiao, Abhijit Parolia, Yuanyuan Qiao, Pushpinder Bawa, Sanjana Eyunni, Rahul Mannan, Sandra E. Carson, Yu Chang, Xiaoju Wang, Yuping Zhang, Josh N. Vo, Steven Kregel, Stephanie A. Simko, Andrew D. Delekta, Mustapha Jaber, Heng Zheng, Ingrid J. Apel, Lisa McMurry, Fengyun Su, Rui Wang, Sylvia Zelenka-Wang, Sanjita Sasmal, Leena Khare, Subhendu Mukherjee, Chandrasekhar Abbineni, Kiran Aithal, Mital S. Bhakta, Jay Ghurye, Xuhong Cao, Nora M. Navone, Alexey I. Nesvizhskii, Rohit Mehra, Ulka Vaishampayan, Marco Blanchette, Yuzhuo Wang, Susanta Samajdar, Murali Ramachandra and Arul M. Chinnaiyan ()
Additional contact information
Lanbo Xiao: University of Michigan
Abhijit Parolia: University of Michigan
Yuanyuan Qiao: University of Michigan
Pushpinder Bawa: University of Michigan
Sanjana Eyunni: University of Michigan
Rahul Mannan: University of Michigan
Sandra E. Carson: University of Michigan
Yu Chang: University of Michigan
Xiaoju Wang: University of Michigan
Yuping Zhang: University of Michigan
Josh N. Vo: University of Michigan
Steven Kregel: University of Michigan
Stephanie A. Simko: University of Michigan
Andrew D. Delekta: University of Michigan
Mustapha Jaber: University of Michigan
Heng Zheng: University of Michigan
Ingrid J. Apel: University of Michigan
Lisa McMurry: University of Michigan
Fengyun Su: University of Michigan
Rui Wang: University of Michigan
Sylvia Zelenka-Wang: University of Michigan
Sanjita Sasmal: Electronic City Phase II
Leena Khare: Electronic City Phase II
Subhendu Mukherjee: Electronic City Phase II
Chandrasekhar Abbineni: Electronic City Phase II
Kiran Aithal: Electronic City Phase II
Mital S. Bhakta: Dovetail Genomics
Jay Ghurye: Dovetail Genomics
Xuhong Cao: University of Michigan
Nora M. Navone: The University of Texas MD Anderson Cancer Center
Alexey I. Nesvizhskii: University of Michigan
Rohit Mehra: University of Michigan
Ulka Vaishampayan: University of Michigan
Marco Blanchette: Dovetail Genomics
Yuzhuo Wang: Vancouver Prostate Centre
Susanta Samajdar: Electronic City Phase II
Murali Ramachandra: Electronic City Phase II
Arul M. Chinnaiyan: University of Michigan

Nature, 2022, vol. 601, issue 7893, 434-439

Abstract: Abstract 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.

Date: 2022
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Citations: View citations in EconPapers (4)

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DOI: 10.1038/s41586-021-04246-z

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