Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer

Lanbo Xiao,Yuping Zhang,Sandra E Carson,Rui Wang,Pushpinder Bawa,Kiran Aithal,Yuzhuo Wang,Xuhong Cao,Heng Zheng,Jay Ghurye,Mustapha Jaber,Sanjita Sasmal,Lisa Mcmurry,Subhendu Mukherjee,Fengyun Su,Alexey I Nesvizhskii,Josh N Vo,Sanjana Eyunni,Yu Sun Chang ,Steven Kregel,Susanta Samajdar,Rahul Mannan,Abhijit Parolia,Andrew Delekta ,Nora M Navone,Rohit Mehra,Stephanie A Simko,Yuanyuan Qiao,Mital S Bhakta,Leena Khare,Xiaoju Wang,Murali Ramachandra,Sylvia Zelenka-Wang,Ingrid J Apel,Chandrasekhar Abbineni,Ulka N Vaishampayan ,Marco Blanchette,Arul M Chinnaiyan

doi:10.1038/s41586-021-04246-z

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.

Highlights

In cancer, genetic alterations invariably lead to an aberrant transcriptional state that is often wired through expansion and remodelling of the enhancer landscape[11,12]
We have developed and characterized a highly-selective proteolysis-targeting chimera (PROTAC) degrader of both SWI/ SNF ATPase subunits—SMARCA2 (BRM) and SMARCA4 (BRG1)—that are required for the nucleosomal-remodelling functions of SWI/SNF complexes
We found enhancer-binding transcription factor-addicted cancers to be exquisitely and preferentially sensitive to SWI/SNF ATPase degradation, which triggered an instantaneous, specific loss of physical accessibility and transcription factor binding at enhancer elements, thereby disrupting enhancer-wired oncogenic gene programs

Summary

Introduction

Genetic alterations invariably lead to an aberrant transcriptional state that is often wired through expansion and remodelling of the enhancer landscape[11,12]. Lung Melanoma Cervical Kidney inhibitors and degraders of ATPase and BRD7–BRD9 SWI/SNF subunits have been recently developed[20,21,22], to our knowledge, no studies have comprehensively assessed the therapeutic efficacy of SWI/SNF inactivation across a wide spectrum of cancers. To this end, we have developed and characterized a highly-selective PROTAC degrader of both SWI/ SNF ATPase subunits—SMARCA2 (BRM) and SMARCA4 (BRG1)—that are required for the nucleosomal-remodelling functions of SWI/SNF complexes. This study is the first preclinical proof of concept that targeted obstruction of chromatin accessibility at enhancer elements may be a potent therapeutic strategy in transcription factor-addicted tumours

Methods

Results

Conclusion