Abstract 1243: Shifted mSWI/SNF complex assembly and function underlie therapeutically targetable dependencies in endometrial carcinoma
Bibliographic record
Abstract
Abstract The mammalian SWI/SNF (mSWI/SNF) family of chromatin remodelers govern cell type-specific chromatin accessibility and gene expression and assemble as three distinct complexes: canonical BAF (cBAF), Polybromo-associated BAF (PBAF), and non-canonical BAF (ncBAF). ARID1A and ARID1B are paralog subunits that specifically nucleate the assembly of cBAF complexes and are the most frequently mutated mSWI/SNF components in human cancer, including in endometrial cancer. However, the biochemical and functional impacts of ARID1A/B loss, and hence cBAF complex disruption, on remaining PBAF and ncBAF complex activities, chromatin architecture, and gene expression remain poorly understood. Here, we define the molecular consequences of complete cBAF loss in models of aggressive de-differentiated endometrial carcinoma (DEC) harboring dual ARID1A/ARID1B mutations. Notably, re-expression of ARID1A in DEC cellular model systems biochemically restores cBAF complex assembly while reducing that of PBAF and ncBAF complexes, implicating functional contributions of differential mSWI/SNF family stoichiometry. We observe genome-wide increases in DNA accessibility at distal enhancer regions following ARID1A rescue, coupled with transcriptional changes at nearest genes including those associated with epithelial lineage differentiation, estrogen receptor signaling, and PI3K/AKT pathway signaling. Importantly, differential gene regulatory changes aligned with simultaneous cBAF restoration and reduction in ncBAF, and PBAF complex function mirror signatures derived from well-differentiated (WEC) and dedifferentiated (DEC) compartments of a collection of n= 15 primary human DEC cases profiled. Reduced ncBAF- and PBAF-mediated chromatin regulation resulting from either ARID1A rescue or ncBAF/PBAF genetic disruption attenuated oncogenic gene signature features such as MYC target genes, cell cycle checkpoint and DNA repair pathways and significantly reduced proliferative capacity. Finally, treatment of ARID1A/1B-mutant and ARID1A-mutant endometrial cell lines in culture and PDX models in vivo with a clinical-grade SMARCA4/2 ATPase inhibitor, FHD-286, markedly attenuated both cell proliferation and tumor growth. Further, FHD-286 synergized with carboplatin, leading to significant reduction in tumor burden in ARID1A- and ARID1A/B-mutant PDX models. Taken together, these findings reveal the oncogenic contributions of shifted of mSWI/SNF family complex abundance and chromatin-level gene regulatory function and suggest therapeutic utility of mSWI/SNF complex small molecule inhibitors in endometrial carcinoma and other cBAF-disrupted cancer types. Citation Format: Jessica Diane St. Laurent, Grace Xu, Alexander Ying, Bengul Gokbayrak, Ajinkya Patil, Akshay Sankar, Chae Young Shin, Daniel Same Guerra, David Kolin, David Huntsman, Yemin Wang, Cigall Kadoch. Shifted mSWI/SNF complex assembly and function underlie therapeutically targetable dependencies in endometrial carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1243.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".