Abstract 5220: Chronic exposure to a novel AR-NTD inhibitor induces resistance via a selective metabolism pathway
Notice bibliographique
Résumé
Abstract Background: The androgen receptor (AR) is recognized as playing a crucial role in prostate cancer (PCa) maintenance and progression; therefore its inhibition has been the cornerstone of modern therapy for men who fail primary treatment. Current treatments are initially effective, however resistance ultimately develops and the disease progresses to a lethal form termed castration-resistant prostate cancer (CRPC). Our lab has discovered a new class of molecules (EPI) which inhibit the AR by binding to the N-terminal domain (NTD). The NTD interacts with transcriptional machinery, and its presence is vital for a transcriptionally functional receptor. We have previously shown that EPI-002 specifically inhibits both full-length AR and constitutively active AR splice variants. The efficacy of EPI-506, the prodrug of EPI-002, is currently being tested in a Phase I/II clinical trial for CRPC. Here we propose novel resistance mechanisms arising from sustained AR-NTD inhibition, with the goal of preemptively developing backup compounds. Methods: The androgen sensitive human PCa cell line LNCaP was used in all experiments. A resistant cell line (LNCaP-EPIR) was generated by passaging parental LNCaP cells weekly in media supplemented with EPI-002 beginning in September 2012. In vitro and in vivo studies using LNCaP and LNCaP-EPIR cells were employed to confirm biological resistance. A human affymetrix microarray identified possible resistance mechanisms and was validated using qRT-PCR, western blot and functional studies. LNCaP and LNCaP-EPIR cells were challenged with EPI-045, an EPI-analog predicted to remain effective in the context of EPI-002 resistance. Results: LNCaP-EPIR cells treated with 25 µM EPI-002 displayed similar growth rates to vehicle treatment, both in vitro and in vivo. Conversely, parental LNCaP cells showed significant growth inhibition in response to EPI-002. LNCaP-EPIR cells retained sensitivity to anti-androgens and AR knock-down by targeted siRNA, implying functional AR remains essential for growth. qRT-PCR data demonstrated that EPI-002 had reduced ability to block AR mediated gene transcription. Interrogation of microarray data revealed candidate genes (UGT2B family) which were specifically upregulated in the resistant line, and may function to metabolize EPI-002. Supporting this hypothesis EPI-045 which is predicted to be resistant to UGT2B metabolism, was able to significantly inhibit LNCaP-EPIR proliferation and AR transcriptional activity. Conclusions: Taken together these data suggest an EPI-specific mechanism of resistance, whereby EPI-002 is preferentially metabolized and removed from the cell. LNCaP-EPIR cells remain dependent upon AR signalling, and are sensitive to anti-androgens used clinically as well as a novel EPI-analog. This work highlights the potential for combination or sequential therapy in the context of drug-resistant CRPC. Citation Format: Jonathon K. Obst, Jun Wang, David Williams, Amy H. Tien, Nasrin R. Mawji, Yu Chi Yang, Raymond J. Andersen, Marianne D. Sadar. Chronic exposure to a novel AR-NTD inhibitor induces resistance via a selective metabolism pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5220. doi:10.1158/1538-7445.AM2017-5220
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 ».