SMARCA2 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A, Member 2)

Immunotherapy and targeted therapies show promise in managing thoracic SMARCA4-UT, warranting further investigation. Further exploring the genetic and molecular landscape of this tumor might reveal potential therapeutic targets.

This work provides further characterization of ICMT as an important CNS mesenchymal neoplasm that is prone to tumor recurrence, showing 2 prognostically relevant methylation subclasses, and warranting diagnostic distinction from other epigenetically and histologically related tumors. ICMTs show substantial overexpression of the CREM gene, independent of fusion type.

In AML with 3q26.2 rearrangements (r) the distal GATA2 hematopoietic enhancer becomes aberrantly relocated leading to activation of EVI1 expression. In patient-derived xenograft (PDX) models of AML with MECOM-r, compared to each drug alone, co-treatment with FHD-286 and BETi OTX015 significantly reduced AML burden and improved survival, without inducing significant toxicity. These findings highlight the FHD-286-based combinations as promising therapy of AML with chromosome 3q26.2 rearrangement and EVI1 overexpression.

UCA1 is known to stimulate proliferation and decrease apoptosis, and we here show that it can restrain cells from a stem cell phenotype. The dual action of UCA1 revealed in this study highlights the complex actions of lncRNAs in cancer.

Proteome-wide degradation selectivity was further characterized by ranking the degraded targets according to the reduction extent of their protein half-lives. Interestingly, the AuPROTAC degraded a relatively limited number of proteins (95) when compared to ACBI2 (221).

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.

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.

This tumor exhibits aggressive clinical behavior, limited availability of targeted therapeutic options, and only modest responses to conventional chemotherapy. The present report underscores the potential efficacy of immune checkpoint inhibitors as a viable treatment modality for SMARCA4-UT.

Co-loss of SWI/SNF and SMARCA2 correlates with poorer prognosis. Comprehensive evaluation of histopathology, immunohistochemistry, and molecular genetics is critical for accurately diagnosing this rare entity.

Grade 3-4 treatment-related adverse events occurred in 37% of both groups. These findings highlight the clinical benefits of subtyping-based precision therapies, particularly for SNF2 and SNF4 subtypes, warranting further validation in phase III trials.

In lung cancer, these strategies show particular promise against KRAS, EGFR, and SMARCA2/4-driven malignancies, while also offering synergy with immunotherapy and chemotherapy. This review highlights current design principles, emerging applications, and future perspectives for conditional and tumor-activated PROTACs, underscoring their transformative potential in precision oncology.