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Published on: April 27, 2018
Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer
Lanbo Xiao1,2, Abhijit Parolia1,2,3, Yuanyuan Qiao1,2,4
1Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
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.
Insights
A novel PROTAC degrader, AU-15330, targets SWI/SNF ATPase subunits SMARCA2 and SMARCA4. This dual degradation shows promise for treating prostate cancer by disrupting oncogenic gene programs and enhancer accessibility.
Area of Science:
- Oncology
- Molecular Biology
- Chromatin Biology
Background:
- The switch/sucrose non-fermentable (SWI/SNF) complex is vital for chromatin remodeling and frequently altered in cancer.
- SMARCA2 and SMARCA4 are ATPase subunits of the SWI/SNF complex implicated in cancer development.
Purpose of the Study:
- To develop and evaluate a PROTAC degrader targeting SMARCA2 and SMARCA4.
- To investigate the therapeutic potential of dual SWI/SNF ATPase degradation in prostate cancer.
Main Methods:
- Development of a PROTAC degrader (AU-15330) targeting SMARCA2 and SMARCA4.
- Assessment of sensitivity in prostate cancer cell lines versus normal and other cancer cell lines.
- Analysis of cis-regulatory element compaction, transcription factor displacement, and gene program disruption.
- Evaluation in prostate cancer xenograft models, including combination therapy with enzalutamide.
Main Results:
- AU-15330 selectively degrades SMARCA2 and SMARCA4 in AR+ FOXA1+ prostate cancer cells.
- Degradation leads to rapid chromatin compaction, dislodging key transcription factors (AR, FOXA1, ERG, MYC).
- AU-15330 inhibits tumor growth, synergizes with enzalutamide, and achieves remission in CRPC models without toxicity.
Conclusions:
- Dual SWI/SNF ATPase degradation is a potent strategy against prostate cancer.
- Targeting SWI/SNF-mediated enhancer accessibility offers a promising therapeutic avenue for enhancer-addicted cancers.
