Targeting of Brahma-related gene-1 (BRG1) overcomes paclitaxel-induced multidrug resistance caused by overexpression of the subset of ATP-binding cassette (ABC) transporters.

Multidrug resistance of cancer cells is attributed to drug-induced alteration of numerous intracellular processes. Using clinically relevant models of triple-negative breast and non-small lung cancer cells we previously showed that these cells respond to repeated paclitaxel exposure by inter alia lysosome enrichment in ABCC3, ABCC5, and ABCC10, which contribute to drug sequestration in these organelles and reduced drug cytotoxicity. In this study, we provide experimental evidence that transcription of the above-mentioned ABCC genes is enabled by BRG1-based SWI/SNF chromatin remodeling complex. Pharmacological inhibition of SWI/SNF with PFI3 or ACBI1, the PROTAC degrader of SMARCA2/4, substantially reduced transcription of ABCC3, ABCC5, and ABCC10. A similar effect was caused by transient silencing of SMARCA4 (BRG1), but not SMARCA2 (BRM). The deficiency of BRG1 led to extralysosomal distribution of anticancer drugs, their deeper penetration of spheroids, and substantial increase in drug cytotoxicity. Interestingly, in BRG1-deficient cell line paclitaxel triggered mutations, which reverted BRG1 truncating deletion in SMARCA4, thereby restoring SWI/SNF ATPase expression in paclitaxel-resistant cells and increasing transcription of ABCC. Acquisition of drug resistance was associated with BRG1 redistribution in the genome, de novo occurrence at the promoters of genes functionally linked to endolysosomal system, and stronger co-occurrence with EP300. Our study indicates possible target--SWI/SNF complex for anticancer combinatorial interventions in paclitaxel-induced multidrug resistant phenotypes. SIGNIFICANCE STATEMENT: This study provides evidence that BRG1 inhibition with PFI3 and degradation of SMARCA4 mRNA substantially declines lysosomal drug sequestration and potentiate drug toxicity. Therefore, BRG1 targeting can be considered as candidate for combinatorial anticancer therapy with some standard chemotherapy drugs.