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; Arul M Chinnaiyan

doi:10.1038/s41586-021-04246-z

Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer

Nature. 2022 Jan;601(7893):434-439. doi: 10.1038/s41586-021-04246-z. Epub 2021 Dec 22.

Authors

Lanbo Xiao^#^{1

2}, Abhijit Parolia^#^{1

2

3}, Yuanyuan Qiao^#^{1

2

4}, Pushpinder Bawa^{1

2}, Sanjana Eyunni^{1

2

3}, Rahul Mannan^{1

2}, Sandra E Carson^{1

2}, Yu Chang^{1

2}, Xiaoju Wang^{1

2

4}, Yuping Zhang^{1

2}, Josh N Vo^{1

2

5}, Steven Kregel^{1

2}, Stephanie A Simko^{1

2}, Andrew D Delekta^{1

2}, Mustapha Jaber¹, Heng Zheng^{1

2}, Ingrid J Apel^{1

2}, Lisa McMurry^{1

2}, Fengyun Su^{1

2}, Rui Wang^{1

2}, Sylvia Zelenka-Wang^{1

2}, Sanjita Sasmal⁶, Leena Khare⁶, Subhendu Mukherjee⁶, Chandrasekhar Abbineni⁶, Kiran Aithal⁶, Mital S Bhakta⁷, Jay Ghurye⁷, Xuhong Cao^{1

2

8}, Nora M Navone⁹, Alexey I Nesvizhskii^{1

2

4

5}, Rohit Mehra^{1

2

4}, Ulka Vaishampayan¹⁰, Marco Blanchette⁷, Yuzhuo Wang^{11

12}, Susanta Samajdar⁶, Murali Ramachandra⁶, Arul M Chinnaiyan^{13

14

15

16

17

18}

Affiliations

¹ Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
² Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
³ Molecular and Cellular Pathology Program, University of Michigan, Ann Arbor, MI, USA.
⁴ Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
⁵ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
⁶ Aurigene Discovery Technologies, Electronic City Phase II, Bangalore, India.
⁷ Dovetail Genomics, Scotts Valley, CA, USA.
⁸ Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, USA.
⁹ 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.
¹⁰ Department of Internal Medicine/Oncology, University of Michigan, Ann Arbor, MI, USA.
¹¹ Vancouver Prostate Centre, Vancouver, British Columbia, Canada.
¹² Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.
¹³ Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA. arul@umich.edu.
¹⁴ Department of Pathology, University of Michigan, Ann Arbor, MI, USA. arul@umich.edu.
¹⁵ Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. arul@umich.edu.
¹⁶ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA. arul@umich.edu.
¹⁷ Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, USA. arul@umich.edu.
¹⁸ Department of Urology, University of Michigan, Ann Arbor, MI, USA. arul@umich.edu.

^# Contributed equally.

Abstract

The switch/sucrose non-fermentable (SWI/SNF) complex has a crucial role in chromatin remodelling¹ 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphatases* / metabolism
Animals
Benzamides
DNA Helicases* / genetics
Enhancer Elements, Genetic
Genes, myc
Hepatocyte Nuclear Factor 3-alpha
Humans
Male
Nitriles
Nuclear Proteins* / genetics
Oncogenes
Phenylthiohydantoin
Prostatic Neoplasms* / drug therapy
Prostatic Neoplasms* / genetics
Receptors, Androgen
Transcription Factors* / genetics
Transcriptional Regulator ERG
Xenograft Model Antitumor Assays

Substances

AR protein, human
Benzamides
ERG protein, human
FOXA1 protein, human
Hepatocyte Nuclear Factor 3-alpha
Nitriles
Nuclear Proteins
Receptors, Androgen
SMARCA2 protein, human
Transcription Factors
Transcriptional Regulator ERG
Phenylthiohydantoin
enzalutamide
Adenosine Triphosphatases
SMARCA4 protein, human
DNA Helicases

Abstract

Publication types

MeSH terms

Substances

Grants and funding