Abstract 443: Targeting therapeutic vulnerabilities mediated by epigenetic reprogramming in ARID1A and ARID1B dual-deficient gynecologic cancers
Notice bibliographique
Résumé
Abstract Background: Dedifferentiated carcinoma of the uterus and the ovary (DDEC collectively) are rare gynecologic cancers made of low-grade differentiated adenocarcinoma of the uterus or ovary juxtaposed against undifferentiated carcinoma. The two components are clonally related, and previous studies have suggested that loss of various switch/sucrose non-fermentable (SWI/SNF) proteins may contribute to the transformation of differentiated cancer cells to an undifferentiated state. Specifically, a third of all DDECs have co-inactivation of cBAF-specific subunits ARID1A and ARID1B. cBAF is one of the three major SWI/SNF complex subfamilies, and loss of ARID1A/B disrupts the chromatin remodeling function of cBAF. We hypothesize that epigenetic reprogramming in response to loss of cBAF activity will alter residual SWI/SNF complex assembly, creating vulnerabilities in DDEC that will allow for novel therapeutic opportunities. Methods: We generated an isogenic cell line with ARID1A/B dual loss to narrow down vulnerabilities in dual-deficient cells. Using this isogenic pair, we conducted a drop-out screen using EPIKOL, a CRISPR knockout library targeting epigenetic modifiers and cofactors. To validate the results, we genomically depleted and treated cells with small molecules to inhibit protein function. Additionally, to further understand the changes in SWI/SNF complex assembly when cBAF is lost, we conducted density gradient sedimentation assays with nuclear protein extracts isolated from the isogenic cell line pair. Finally, SWI/SNF inhibitors were added to bona fide ARID1A/B dual-deficient dedifferentiated carcinoma of the uterus and the ovary cell lines and xenografted tumors to test the generalizability of our findings. Results: EPIKOL screening identified that ARID1B-dependent, ARID1A-deficient cancer cells have increased reliance on ARID2 and PBRM1, two PBAF-specific subunits, upon ARID1B deletion. When ARID2 and PBRM1 were knocked out in ARID1A proficient and ARID1A/B dual-deficient cells, the latter had significant growth impairment. Furthermore, when treating the isogenic cell line pair with SWI/SNF inhibitors, we also noted increased sensitivity in the dual-deficient cell line. Moreover, we observed a shift towards PBAF assembly in the cells with ARID1A/B dual-loss, further supporting an increased dependency on the remaining SWI/SNF complexes in dual-deficient cells. Finally, we observed increased sensitivities towards SWI/SNF subunit inhibitors in other ARID1A/B dual-deficient ovarian and endometrial cancer cell lines and their xenografted tumors. Conclusion: ARID1A/B dual-deficient cancer cells have an increased reliance on the remaining SWI/SNF complexes for survival, thus highlighting a novel therapeutic option for DDEC with ARID1A/B dual loss. Citation Format: Rebecca Ho, Bengul Gokbayrak, Eunice Li, Shary Chen, Emma Guo, Chae Young Shin, David Huntsman, Nathan Lack, Yemin Wang. Targeting therapeutic vulnerabilities mediated by epigenetic reprogramming in ARID1A and ARID1B dual-deficient gynecologic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 443.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».