Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer

• Published in: Nature (London) 2022-01, Vol.601 (7893), p.434-439
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: 13/106; 38/15; 38/23; 38/39; 38/91; 631/337/100/102; 631/67/1059/602; 631/67/589/466; Adenosine triphosphatase; Adenosine Triphosphatases - metabolism; Androgen receptors; Animals; Benzamides; Castration; Cell proliferation; Chromatin; Circuits; Compacts; Degradation; DNA Helicases - genetics; Enhancer Elements, Genetic; Forkhead protein; Gene expression; Genes, myc; Hepatocyte Nuclear Factor 3-alpha; Humanities and Social Sciences; Humans; Ligands; Male; Mass spectrometry; multidisciplinary; Myc protein; Nitriles; Nuclear Proteins - genetics; Oncogenes; Phenylthiohydantoin; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; Proteins; Proteolysis; Receptors, Androgen; Regulatory sequences; Remission; RNA polymerase; Science; Science (multidisciplinary); Scientific imaging; Sucrose; Toxicity; Transcription factors; Transcription Factors - genetics; Transcriptional Regulator ERG; Tumor cell lines; Tumors; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-021-04246-z

The switch/sucrose non-fermentable (SWI/SNF) complex has a crucial role in chromatin remodelling 1 and is altered in over 20% of cancers 2 , 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. PROTAC degrader–induced SWI/SNF inactivation abolishes DNA accessibility at enhancer elements of oncogenes and also tempers supra-physiologic expression of driver transcription factors, resulting in potent inhibition of tumour growth in mouse models.