Abstract PO-053: Chemical suppression of DHFR induces NRF2 inhibition and tumor regression
Notice bibliographique
Résumé
Abstract Background: Recurrence in head and neck squamous cell carcinoma (HNSCC) is common due to primary resistance and acquired resistance arising during therapy. Recent studies have highlighted a critical role of NRF2 in radiation (RT) resistance. Constitutive activation of the NRF2 oxidative stress response pathway occurs in 20-30% of primary HNSCC. As a ROS-activated transcription factor that is frequently mutated and active in cancer, NRF2 is central to both intrinsic and acquired determinants of RT resistance. We recently showed that high NRF2 activity is predictive for locoregional failure and poor outcomes following RT in HNSCC. The downstream effectors of NRF2 responsible for RT resistance are poorly defined. Therapeutic strategies to inhibit NRF2 may improve HNSCC patient outcomes, yet remain unproven. Methods: We sought to study NRF2 activation and biology in two model systems: MOC1 syngeneic HNSCC cells and mouse embryonic fibroblasts (MEFs) derived from a NRF2E79Q genetically engineered mouse model. We defined a transcriptional signature associated with an activating NRF2 mutation (NRF2E79Q) and characterized the effect of NRF2 on cell growth and RT response. We also investigated a novel NRF2 inhibitor in the syngeneic mouse MOC1 model. MEFs were isolated from a pregnant mouse, immortalized and selectively infected with 500-800 MOI of Adenovirus Cre-Recombinase for in vitro proliferation and RT assays. Drug studies were performed at 50mM in vitro or 20mg/kg PO daily starting day 7 in vivo. RT was delivered at 0, 4Gy, or 8Gy in vitro or 3Gy daily x 5 days starting day 17 in vivo. Results: RNA isolated from NRF2E79Q MEFs demonstrated activation of numerous oxidative stress pathway transcripts including canonical targets HMOX1, NQO1, BLVRB, and SLC71a11. NRF2E79Q MEFs demonstrated significantly enhanced baseline growth kinetics and RT resistance relative to the NRF2-wildtype line. We recently reported that pyrimethamine—an FDA-approved antiparasitic drug that targets one carbon metabolism— [1.2uM] induced NRF2 ubiquitylation and degradation in vitro and in vivo. Through structure-activity relationship optimization we have produced a novel analogue, [WCDD115; 50nM], with efficacious DHFR suppression and NRF2 inhibition in human and mouse HNSCC cell lines. In vitro, WCDD115 produced growth suppression in the MOC1 cell line which was enhanced in the setting of RT relative to either treatment alone. MOC1-bearing mice treated with WCDD115 or RT as monotherapy had significant reduction in growth kinetics relative to vehicle control. WCDD115 and RT combination therapy produced the greatest effect with significant growth suppression and 25% tumor rejection without weight loss or toxicity. Conclusions: Our study demonstrates that NRF2E79Q mutation is associated with enhanced growth kinetics and RT resistance along with upregulation of oxidative stress pathway targets. Drug targeting with the novel NRF2 inhibitor, WCDD115, has significant tumor suppressive activity in vitro and in vivo and warrants further investigation as a RT-sensitizing agent. Citation Format: Paul Zolkind, Harit Panda, Caroline Krall, Brittany Bowman, Nathan Wamsley, Bernard Weissman, Ben Major. Chemical suppression of DHFR induces NRF2 inhibition and tumor regression [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-053.
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) | 0,004 | 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 ».