A new study has revealed how a key complex that facilitates access to enhancers could be targeted to treat over 90% of prostate cancers.
Gene expression and enhancer remodelling
The process of gene expression is regulated by the modification of physical accessibility to DNA. This process occurs through nucleosomal remodelling and binding of transcription factors. Enhancers are key hubs for transcription factor binding and the activation of lineage-specific gene programs.
A key component of cancer is an aberrant transcriptional state caused by genetic alterations. This is ultimately wired through remodelling of the enhancer landscape. This includes the formation of new enhancers, enhancer hijacking and abnormal enhancer-promoter interactions. All of these alterations enable hyper-expression of driver oncogenes. While targeting such aberrant enhancer function has seen interest, the molecular machinery underpinning enhancer maintenance and function remain poorly characterised.
More recently, researchers have found that alterations in genes encoding constituent subunits of the SWI/SNF complex are present in over 20% of human cancers. SWI/SNF is a multi-subunit chromatin remodelling complex. A key subunit of this complex provides energy to unravel DNA and provide access to enhancer elements. Although it is thought that SWI/SNF-mutant tumours enable oncogenic transcriptional programs, no studies have comprehensively explored the therapeutic efficacy of inactivating this complex across a range of cancers.
Targeting the SWI/SNF complex
In a recent study, published in Nature, researchers developed a highly-selective PROTAC degrader of both SWI/SNF ATPase subunits, SMARCA2 and SMARCA4, that are key for its remodelling functions.
The team looked at several prostate cancer models that expressed different oncogenes. They found that the degrader, called AU-15330, slowed cancer cell growth and induced cell death. This was particularly the case in tumours driven by FOXA1 or androgen receptor. Meanwhile, there was no effect on benign prostate cells. The loss of the SWI/SNF complex, more specifically, resulted in loss of physical accessibility and transcription factor binding at enhancer elements. This in turn disrupted enhancer-wired oncogenic gene programs.
Study author, Arul M. Chinnaiyan, explained:
“Without having mutations, and with just oncogenic transcription factors involved, prostate cancer cells were exquisitely sensitive to this degrader, even more so than lung cancer where a component of the pathway was mutated.
By disabling this SWI/SNF complex, we saw preferential activity against certain cancers and no toxicity in normal cells or normal tissues. This bodes well for clinical studies using compounds that target this pathway.”
Overall, this study has found that enhancer-addicted cancers are preferentially sensitive to SWI/SNF complex degradation. The authors also noted that this is the first preclinical proof of concept that targeting chromatin accessibility at enhancer elements may be a potent therapeutic approach for transcription factor-addicted tumours.
Image credit: canva
