Transcriptional profiling of matched biopsies reveals molecular determinants of enzalutamide resistance.
Notice bibliographique
Résumé
5058 Background: Castration-resistant prostate cancer (CRPC) is the lethal form of the disease. One of the principal therapies in CRPC is the potent androgen receptor (AR) signaling inhibitor enzalutamide (enza). Most patients benefit from enza, but disease progression is nearly universal. A variety of resistance mechanisms have been described by comparing enza-naïve and enza-resistant tumors. However, these results are largely from different groups of patients and do not provide information on the changes induced by enza within a given patient. Lineage plasticity—most commonly-exemplified by loss of AR signaling and switch from a luminal to an alternate differentiation program—is a particularly aggressive resistance mechanism. Importantly, lineage plasticity appears to be increasing in incidence since more widespread use of potent AR signaling inhibitors such as enza. To improve our understanding of resistance mechanisms induced by enza treatment, we analyzed the transcriptomes of matched metastatic CRPC patient biopsies obtained prior to treatment and at the time of disease progression. Methods: All biopsies were obtained as part of the Stand Up 2 Cancer/Prostate Cancer Foundation-funded West Coast Dream Team, a prospective, IRB-approved protocol focused on understanding the biology of metastatic CRPC. We identified 21 patients for whom matched tumor biopsies with RNA-seq were available prior to starting treatment with enza and at the time of progression while still taking enza. Results: Our RNA-seq analysis demonstrates that the majority of progression tumors cluster with their baseline pair, suggesting that enza does not markedly change the tumor transcriptome in most cases. Three of 21 patients showed evidence of lineage plasticity at progression by gene expression analysis. By analyzing the RNA-seq data, we identified pathways linked to stemness that were more activated in baseline tumors from patients whose progression tumors underwent lineage plasticity. Furthermore, we identified a gene signature enriched in these baseline tumors that was associated with risk of lineage plasticity after enza treatment. We determined that high expression of this signature was strongly associated with poor survival from the time of AR signaling inhibitor treatment in independent patient samples, suggesting this signature is linked to poor patient outcome. Conclusions: Enza-resistant tumors are heterogeneous. Most tumors do not undergo significant transcriptional changes at progression vs. baseline. Matching recent reports, approximately 15% of tumors underwent lineage plasticity upon progression. Our work implicates a gene program that may predispose tumors to enza-induced lineage plasticity. Finally, the gene signature we identified may be a marker of lineage plasticity risk and tumor aggressiveness in CRPC prior to the initiation of AR signaling inhibitor therapy.
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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) | 0,002 | 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 ».