Selected Articles from This Issue

The aggressive phenotype of atypical teratoid rhabdoid tumor (ATRT) is driven by the loss of SMARCB1, but the cooperating epigenetic factors remain largely unstudied. To address this, Alimova and colleagues performed an epigenome screening on ATRT SMARCB1-deficient MAF737 cells and identified SIRT2 as a key regulatory molecule. In vitro and in vivo studies using SIRT2 deficient or sufficient cells further demonstrated the functional impact of SIRT2, showing that its expression supports tumor establishment and progression. RNA sequencing of SMARCB1-deficient ATRT cells either treated with a SIRT2 inhibitor or genetically deficient for SIRT2 also revealed an enrichment of differentially expressed genes involved in cell differentiation, and a decrease in genes involved in self-renewal. Interestingly, CUT and RUN assays followed by pathway analysis showed increased H3K27ac marks at the SMARCA4 gene promoter, indicating that SIRT2 may activate the SWI/SNF complex under SMARCB1 deficiency. Treating orthotopic xenografts, the authors also illustrated the potential utility of targeting SIRT2 in ATRT to overcome the effects mediated by SMARCB1 loss, altogether highlighting the importance of SIRT2 in ATRT.The cooperativity of oncoproteins KRAS and p53 is a widely observed phenomenon among cancers. However, the mechanism of their interaction is not well understood. In their study, Ray and colleagues evaluated the interaction between SMURF2, a mutant KRAS stabilizer, and GAP17-1 to better understand the mechanism of mutant KRAS hyperactivation. Immunoprecipitation and cell fractionation studies using cells expressing mutated GAP17-1 (PPLP to AALA) motif showed that the PPLP motif is key to GAP17-1/SMURF2 interaction. Further analysis using a pull-down assay demonstrated that the specific interaction between SMURF2 and the PPLP motif is needed for GAP17-1 membrane displacement, which leads to mutant KRAS hyperactivation. The authors also assessed the role of SMURF2 in p53-KRAS driven oncogenesis through multiple mutant KRASG12D and Trp53R172H mouse models, revealing heightened pro-tumoral phenotypes and synergistic action between mutant KRAS and SMURF2, especially in cases when p53 is also mutated. Analysis of KRASG12DSMURF2 knockdown cells treated with KRASG12D inhibitor MRTX1133 supported these findings, showing that SMURF2 knockdown promoted the efficacy of the inhibitor. Overall, this study demonstrates that SMURF2 promotes mutant KRAS hyperactivation and cancer progression through binding and displacement of GAP17-1 from the membrane and indicates that SMURF2 may have potential as a therapeutic target.Tumor-initiating cells (TIC) present a barrier to successful treatment across cancer types, yet our understanding of their function and generation is limited. To investigate the mechanism of TICs in small cell lung cancer (SCLC), Chatterjee and colleagues evaluated KSR1 for its involvement in tumor initiation and drug resistance. Single cell colony formation assays using KSR1 proficient and deficient SCLC cells demonstrated a decrease in colony formation potential upon KSR1 loss across SCLC subtypes. ELDA further showed that KSR1 deficiency limited the frequency of TICs across SCLC subtypes, which was remediated by restoration of KSR1 expression, altogether indicating a dependency on KSR1 for TIC formation. The authors also analyzed the contribution of ERK signaling pathways in KSR1 function using KSR1-deficient cells transfected with a mutant KSR1 transgene incapable of ERK binding and an ERK inhibitor, finding that KSR1-mediated interaction with ERK, but not ERK kinase activity, is required for proper colony formation and TIC formation. Additionally, KSR1-deficient cells treated with cisplatin exhibited increased levels of TIC cell death in cell viability assays and highlighted the importance of KSR1-regulated ERK signaling in cisplatin resistance. Taken together, this study presents KSR1 as an important mediator of TIC formation and SCLC cisplatin resistance, calling attention to its potential as a novel therapeutic target to advance the treatment of cisplatin-resistant SCLC tumors.