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.
Nature. 2021 Dec 22 [Epub ahead of print]
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, Arul M Chinnaiyan
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA., Aurigene Discovery Technologies, Electronic City Phase II, Bangalore, India., Dovetail Genomics, Scotts Valley, CA, USA., Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Department of Internal Medicine/Oncology, University of Michigan, Ann Arbor, MI, USA., Vancouver Prostate Centre, Vancouver, British Columbia, Canada., Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA. .