Abstract 5511: Investigating Wee1 and Myt1 combined inhibition as a potential cancer therapeutic strategy
Notice bibliographique
Résumé
Abstract Introduction: Cell cycle is under the surveillance of checkpoints to repair any damage before the cell transits between phases. Wee1 and Myt1 kinases prevent premature entry into mitosis by monitoring the G2/M checkpoint by adding an inhibitory phosphorylation on Cdk1. Wee1 is overexpressed in various tumors and MK-1775, a Wee1 small molecule inhibitor, is currently in phase I/II cancer clinical trials. Although MK-1775 was shown to potentiate the effect of other genotoxic therapies, yet clinical resistance has emerged towards it. In examining the mechanism of MK-1775-mediated cytotoxicity, we identified Myt1 as a resistant factor. Emerging evidence suggests that Myt1 is an important cancer therapeutic target. Hence, we are examining a novel Myt1 kinase small molecule inhibitor, RP-6306 in combination with MK-1775 as a potential synthetic lethal cancer therapy. We hypothesize that a combination of MK-1775 and RP-6306, inhibitors against two partially redundant kinases important for adaptation to genotoxic stress, will achieve synthetic lethality while circumventing the issue of resistance development following monotherapies. Model Systems Used: 1) a cervical cancer cell line that is tetracycline inducible for Myt1 expression; 2) cancer cell lines (breast and cervical) that are resistant to MK-1775 through upregulation of Myt1. Methods: We established the IC50 of RP-6306 in a panel of tumorigenic and non-tumorigenic cell lines using standard crystal violet viability assay. Following that, we tested the combination effect of MK-1775 and RP-6306 in model cell lines listed above using zero potency model of synergy. The effect of the combination treatment on the clonogenicity was evaluated using clonogenic assay. Timelapse microscopy on a High Content Imaging system was used to determine the effect of RP-6306 and MK-1775 on mitotic duration and cell fates. Results: We found that MK-1775 and RP-6306 combination treatment shows synergistic cell killing in a panel of cancer cell lines. Wee1 inhibition shows synergistic cell killing with Myt1 inhibition especially in inducible Myt1 overexpressing cells. Wee1 and Myt1 combined inhibition resists the increase in clonogenic potential of the cancer cells transiently overexpressing Myt1. RP-6306 and MK-1775 combination treatment promotes mitotic arrest leading to cell death in Myt1 overexpressing cells. We also found that the mechanism of cell death in the cells treated with the combination treatment is centromere fragmentation leading to mitotic catastrophe. Conclusions: The combined Wee1 and Myt1 inhibition leads to synthetic lethality. Hence, our findings strongly suggest that the combined MK-1775 and RP-6306 treatment has promising potential to mitigate MK-1775 resistance. Our research contributes to the development of novel potential combination therapy while optimizing and improving the efficacy of MK-1775 treatment for potential clinical use. Citation Format: Sargun Sokhi, Joanne D. Hadfield, Jeremy Fung, Gordon K. Chan. Investigating Wee1 and Myt1 combined inhibition as a potential cancer therapeutic strategy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5511.
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) | 0,001 | 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) | 0,003 | 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 ».