SMARCA4/BRG1 deficiency induces a targetable dependence on oxidative phosphorylation in clear cell renal cell carcinoma

The tumor suppressor gene SMARCA4, a critical component of the SWI/SNF chromatin remodeling complex, is frequently inactivated in various cancers, including clear cell renal cell carcinoma (ccRCC). Despite its significance, the role of SMARCA4 in ccRCC development and its potential therapeutic vulnerabilities have not been fully explored. Our research found that SMARCA4 deficiency was associated with poor prognosis and was observed in a subset of high-grade ccRCCs. Through functional assays, we determined that the suppression of SMARCA4 led to an increase in RCC cell proliferation. Further gene expression analysis unveiled that SMARCA4-deficient cells exhibit an upregulation of the oxidative phosphorylation (OXPHOS) pathway. Delving deeper, we combined RNA sequencing (RNA-Seq) and Assay for transposase-accessible chromatin with sequencing (ATAC-Seq) data to uncover that SMARCA4 plays a crucial role in modulating chromatin accessibility and the expression of genes essential for the respiratory electron transport chain. A significant finding from our study is that RCC cells and xenograft tumors lacking SMARCA4 demonstrated an increased sensitivity to the inhibition of the OXPHOS pathway by the novel small molecule IACS-010759. This sensitivity is attributed to the heightened energy demands and susceptibility to energy stress observed in SMARCA4-deficient cells, driven by their amplified biosynthetic requirements. The efficacy of IACS-010759 stems from its ability to induce energy deprivation, pinpointing OXPHOS inhibition as a promising therapeutic approach for targeting SMARCA4-mutant tumors. This strategy offers a novel avenue to address a currently unmet therapeutic need, highlighting the potential of OXPHOS inhibition in the treatment of cancers harboring SMARCA4 mutations.