Abstract A033: Identity fraud: Lineage plasticity as a mechanism of antiandrogen resistance and target for therapy
Notice bibliographique
Résumé
Abstract Background: Potent targeting of the androgen receptor (AR) in castration-resistant prostate cancer has altered the archetypal course of the disease, fueling the emergence of aggressive and incurable neuroendocrine prostate cancer (NEPC). Recent evidence suggests that these tumors can arise from non-neuroendocrine cells in response to AR pathway inhibitors (ARPIs), such as enzalutamide (ENZ), an observation consistent with lineage plasticity. What regulates this plasticity that allows cells to shed their dependence on the AR and re-emerge as “AR-indifferent” NEPC? Sequencing studies have uncovered that the evolution toward a NEPC phenotype is aligned with dynamic epigenetic reprogramming, but the molecular basis underlying this phenomenon remains poorly understood. Methods: We developed an in vivo model of acquired ENZ resistance to (a) identify reprogramming factors that facilitate lineage plasticity, and (b) determine how to best capitalize on therapeutic strategies aimed at blocking or reversing lineage transformation. Cell lines derived from ENZ-resistant tumors were profiled by RNA-seq and ChIP-seq, and functionally assessed for stem cell-associated properties. Our findings were validated across NEPC cell lines (NCI-H660), genetically engineered mouse models (PBCre4:Ptenf/f:Rb1f/f), and patient tumors and organoids. CRISPR/Cas9-mediated genomic editing allowed us to assess the effect of knocking out reprogramming factors on therapy-induced neuroendocrine transdifferentiation. Results: AR-indifferent ENZ-resistant tumors were enriched for a Polycomb/EZH2 signature; in particular, we identified EZH2 to be phosphorylated at threonine-350 (pEZH2-T350) by CDK1 in NEPC cell lines, mouse models, and patient tumors. Accordingly, RB1 loss was sufficient to enhance pEZH2-T350, which was required for prostate cancer cells to convert to a metastable stem-like state and, in turn, acquire neuroendocrine features under the pressure of ARPIs both in vitro and in patient-derived xenografts. This therapy-induced NEPC transdifferentation was associated with a marked redistribution of EZH2 and H3K27me3, specifically to a core set of genes governing lineage identity. AR colocalized at the reprogrammed EZH2 binding sites, and was found to be part of the same complex with EZH2. Treating AR-indifferent/NEPC cell lines with clinically relevant EZH2 inhibitors reversed the lineage switch and mitigated ENZ resistance. Conclusions: This research establishes the centrality of epigenetic reprogramming in driving the insurgence of a neuroendocrine phenotype in response to ARPIs, and posits that drugging the epigenome via EZH2 inhibition may reverse or delay lineage transformation to extend the durability of clinically beneficial ARPIs. Citation Format: Alastair Davies, Chiara Bostock, Musaddeque Ahmed, Yen-Yi Lin, Fraser Johnson, Ka Mun Nip, Kirsi Ketola, Jennifer Bishop, Ladan Fazli, David Goodrich, Faraz Hach, Hansen He, Himisha Beltran, Amina Zoubeidi. Identity fraud: Lineage plasticity as a mechanism of antiandrogen resistance and target for therapy [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A033.
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 | 0,001 | 0,000 |
| Science ouverte | 0,001 | 0,001 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,007 | 0,002 |
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 ».