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Multi-subunit ATPase-dependent chromatin remodelling complexes SWI/SNF (switch/sucrose non-fermentable) are fundamental epigenetic regulators of gene transcription. Functional genomic studies revealed a remarkable mutation prevalence of SWI/SNF-encoding genes in 20–25% of all human cancers, frequently driving oncogenic programmes. Some SWI/SNF-mutant cancers are hypersensitive to perturbations in other SWI/SNF subunits, regulatory proteins and distinct biological pathways, often resulting in sustained anticancer effects and synthetic lethal interactions. Exploiting these vulnerabilities is a promising therapeutic strategy. Here, we review the importance of SWI/SNF chromatin remodellers in gene regulation as well as mechanisms leading to assembly defects and their role in cancer development. We will focus in particular on emerging strategies for the targeted therapy of SWI/SNF-deficient cancers using chemical probes, including proteolysis targeting chimeras, to induce synthetic lethality.
BH3 mimetics are promising novel anticancer therapeutics. By selectively inhibiting BCL-2, BCL-xL, or MCL-1 (i.e. ABT-199, A-1331852, S63845) they shift the balance of pro- and anti-apoptotic proteins in favor of apoptosis. As Bromodomain and Extra Terminal (BET) protein inhibitors promote pro-apoptotic rebalancing, we evaluated the potential of the BET inhibitor JQ1 in combination with ABT-199, A-1331852 or S63845 in rhabdomyosarcoma (RMS) cells. The strongest synergistic interaction was identified for JQ1/A-1331852 and JQ1/S63845 co-treatment, which reduced cell viability and long-term clonogenic survival. Mechanistic studies revealed that JQ1 upregulated BIM and NOXA accompanied by downregulation of BCL-xL, promoting pro-apoptotic rebalancing of BCL-2 proteins. JQ1/A-1331852 and JQ1/S63845 co-treatment enhanced this pro-apoptotic rebalancing and triggered BAK- and BAX-dependent apoptosis since a) genetic silencing of BIM, BAK or BAX, b) inhibition of caspase activity with zVAD.fmk and c) overexpression of BCL-2 all rescued JQ1/A-1331852- and JQ1/S63845-induced cell death. Interestingly, NOXA played a different role in both treatments, as genetic silencing of NOXA significantly rescued from JQ1/A-1331852-mediated apoptosis but not from JQ1/S63845-mediated apoptosis. In summary, JQ1/A-1331852 and JQ1/S63845 co-treatment represent new promising therapeutic strategies to synergistically trigger mitochondrial apoptosis in RMS.