Abstract 5394: Uterine leiomyosarcoma with homologous recombination deficiency is highly sensitive to polo-like kinase 4 inhibitor
Notice bibliographique
Résumé
Abstract INTRODUCTION: Uterine leiomyosarcoma (LMS) is rare and aggressive and without a well-established cancer-driver. Treatment is mainly surgical because most other therapies have limited benefits. Polo-like kinase 4 (PLK4) is a modulator of centriole duplication that is essential for proper cell division. Its inhibition by the PLK4 inhibitor, CFI-400945 resulted in centriole dysregulation, increased in double-strand DNA damage, and ultimately, mitotic catastrophe and cell death. Recent genomic studies have identified a subset of LMS with homologous recombination (HR) repair deficiency. We hypothesize that HR-deficient LMS is highly sensitive to CFI-400945. METHODS: Gene knockouts (KO) were done by CRISPR-Cas9 system. Plasmids encoding the BRCA1- and BRCA2-targeting guide RNA, Cas9 protein, and selection markers were generated and were transfected into SK-UT-1 and SKN followed by selection with antibiotics. The KO and wild-type cell lines were treated with CFI-400945 in vitro. Percentage apoptosis was evaluated by Annexin V-PI staining and cell proliferation was examined by sulforhodamine B assay. To determine whether BRCA1- and BRCA2-KO had any effects on double-strand DNA damage, the γH2AX foci were studied by immunofluorescence staining. RESULTS: CFI-400945 caused a greater degree of apoptosis and less cell viability in the KO than in the wild-type cell lines. In SK-UT-1, quantity of apoptotic cells for BRCA2-KO and BRCA1-KO were 77% and 34%, respectively, versus 27% in the wild-type cell line (p<0.05). Less dramatic findings were observed in SKN with respective percentages of 20% and 25% versus 15% (p<0.05). In SK-UT-1, the mean IC50 for BRCA2-KO and BRCA1-KO were 3.4 nM and 5.5 nM, respectively, versus 7.8 nM in the wild-type cell line (p<0.05). Similar observations were noted in SKN, with respective mean IC50 of 6.5 nM and 7.1 nM versus 10.0 nM (p<0.05). After CFI-400945 treatment, the γH2AX/Hoechst 33342 staining intensity ratio was 0.40 in SK-UT-1 BRAC2-KO and 0.44 in BRCA1-KO, where both were higher than in the corresponding wild-type cell line with 0.29 (p<0.05). Similarly, the intensities in the two SKN KO cell lines were 0.29 and 0.31, respectively, and higher than in the wild-type cell line with 0.19 (p <0.05). CONCLUSIONS: PLK4 inhibitor induced DNA double-strand breaks in LMS and the repair of these breakages was dependent on HR repair. In vitro, LMS with BRCA1 or BRCA2 deficiencies were more sensitive to the effect of PLK4 inhibitor. Citation Format: Tsz Yan Chong, Horace HY Lee, Judy WP Yam, Kin Long Chow, Ho Shing Wong, Ka Yu Tse, Mark R. Bray, Tak Wah Mak, Philip PC Ip. Uterine leiomyosarcoma with homologous recombination deficiency is highly sensitive to polo-like kinase 4 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5394.
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 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,001 |
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 ».