SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4)

Multivariate analysis confirmed that both advanced FIGO stage and loss of SMARCA4 were independent adverse prognostic factors. This study demonstrates the clinical utility of SWI/SNF complex evaluation, wherein SMARCA4 loss specifically pinpoints an aggressive tumor subset, providing a crucial tool for risk stratification.

The recent patent data show how selective BRD9 degraders represent a significant step forward in terms of efficacy and selectivity, with promising results in preclinical models of acute myeloid leukemia (AML), synovial sarcoma (SS), and Huntington's disease (HD). Despite several critical issues, the selective degradation of this epigenetic target shows great potential to be an innovative therapeutic strategy.

Both tumors exhibited aggressive behavior with rapid local recurrence or metastasis of the undifferentiated carcinoma component. PVs in SWI/SNF genes may be associated with the process of dedifferentiation.

This molecular signature implies potential synergistic effects between chromatin instability, compromised DNA damage repair mechanisms, and augmented immunogenicity. Through comprehensive genomic analysis, we elucidate the biological significance of this mutational landscape and discuss its therapeutic implications, aiming to advance precision diagnosis and guide innovative treatment strategies for SMARCA4-DNSCLC.

Therapeutically, KIF20A inhibition sensitizes TNBC xenografts to standard-of-care chemotherapy. Our study highlights the importance of targeting KIF20A to exploit BCSC vulnerabilities in TNBC.

A growing body of evidence indicates that BAF complex mutations have important prognostic implications. These may be leveraged for risk stratification and therapeutic selection in patients with non-small cell lung cancer.

Next-generation sequencing of the primary small intestinal tumor identified pathogenic mutations in PTEN, TP53, ataxia telangiectasia mutated, ephrin type-A receptor 5 and EGFR p.F997L, suggesting a DNA-repair-deficient genomic background and providing potential targets for future precision therapy. Further research is warranted to determine the molecular mechanisms underlying SMARCA4-DUC, for the development of targeted therapeutic strategies and to improve the understanding of the aggressiveness of SMARCA4-DUC.

There is currently no standard drug treatment regimen for SMARCA4-dTTs, but patients who receive treatment derive some survival benefits. Future research is needed to explore more effective treatment strategies.

Differential considerations, including epithelioid sarcoma, poorly differentiated chordoma, CRINET, choroid plexus carcinoma, and rare composite tumors, further complicate the diagnostic landscape. A comprehensive, multimodal diagnostic approach combining histologic, immunophenotypic, and molecular data is essential to accurately identify AT/RT and guide clinical management, particularly in diagnostically ambiguous or atypical cases.

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.

These include heterogeneous therapeutic responses across tumor types, safety concerns associated with synthetic lethality-based agents, and the absence of any histology-agnostic approved therapy for SMARCA4-deficient tumors. The continued development of novel therapeutics and further large-scale clinical evaluations are essential to overcoming these barriers.