Data from SIRT2 Regulates the SMARCB1 Loss-Driven Differentiation Block in ATRT

<div>Abstract<p>An atypical teratoid rhabdoid tumor (ATRT) is a highly aggressive pediatric brain tumor driven by the loss of<i> SMARCB1</i>, which results in epigenetic dysregulation of the genome. <i>SMARCB1</i> loss affects lineage commitment and differentiation by controlling gene expression. We hypothesized that additional epigenetic factors cooperate with <i>SMARCB1</i> loss to control cell self-renewal and drive ATRT. We performed an unbiased epigenome-targeted screen to identify genes that cooperate with <i>SMARCB1</i> and identified <i>SIRT2</i> as a key regulator. Using <i>in vitro</i> pluripotency assays combined with <i>in vivo</i> single-cell RNA transcriptomics, we examined the impact of <i>SIRT2</i> on differentiation of ATRT cells. We used a series of orthotopic murine models treated with <i>SIRT2</i> inhibitors to examine the impact on survival and clinical applicability. We found that ATRT cells are highly dependent on <i>SIRT2</i> for survival. Genetic or chemical inhibition led to decreased cell self-renewal and induction of differentiation in tumor spheres and <i>in vivo</i> models. We found that<i> SIRT2 </i>inhibition can restore gene expression programs lost because of <i>SMARCB1</i> loss and reverse the differentiation block in ATRT <i>in vivo</i>. Finally, we showed the <i>in vivo</i> efficacy of a clinically relevant inhibitor demonstrating<i> SIRT2</i> inhibition as a potential therapeutic strategy. We concluded that <i>SIRT2</i> is a critical dependency in <i>SMARCB1</i>-deficient ATRT cells and acts by controlling the pluripotency–differentiation switch. Thus, <i>SIRT2</i> inhibition is a promising therapeutic approach that warrants further investigation and clinical development.</p>Implications:<p><i>SIRT2</i> inhibition is a molecular vulnerability in <i>SMARCB1</i>-deleted tumors.</p></div>