Alterations in genes encoding subunits of switch/sucrose non-fermentable (SWI/SNF) complex have been found to be present in over 20% of human cancers: it’s a chromatin remodelling complex and a key subunit of the complex provides energy to unravel DNA and provide access to enhancer elements. A new study recently published on Nature showed that a degradation of SWI/SNF complex subunits resulted in loss of physical accessibility and transcription factor binding at enhancer elements, which in turn disrupted enhancer-wired oncogenic gene programs.
Authors developed a highly-selective PROTAC degrader of both SWI/SNF ATPase subunits that are key for its remodelling functions; they tested the degrader, called AU-15330, in several prostate cancer models that expressed different oncogenes and found that the strategy slowed cancer cell growth and induced cell death, particularly in tumors driven by androgen receptors, with no effect on normal prostate cells. Findings show that enhancer-addicted cancers are preferentially sensitive to SWI/SNF complex degradation and 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 tumors. «Prostate cancer cells were sensitive to this degrader: by disabling this SWI/SNF complex, we saw preferential activity against certain cancers and no toxicity in normal cells or normal tissues. Clinical studies using compounds that target this pathway could be relevant», said study author Arul Chinnaiyan.
