Abstract B090: Targeting the unfolded protein response enhances sensitivity to chemotherapy
Notice bibliographique
Résumé
Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is currently the 3rd leading cause of cancer-related deaths in North American with ~10% survival 5 years after diagnosis. A contributing factor to this low survival rate is chemotherapy resistance. Major risk factors for PDAC, including smoking and chronic pancreatitis, promote activation of the unfolded protein response (UPR). The UPR reduces protein load to alleviate stress, and cancer cells can utilize the UPR to promote cell survival. We previously showed loss of Activating Transcription Factor 3 (ATF3), a mediator of the UPR, restricted early events in PDAC progression. The goal of this study was to determine if ATF3 and the UPR promote resistance to chemotherapy in PDAC. We hypothesized that cancer cells activate the UPR and ATF3 to reduce cell stress and promote chemotherapeutic resistance. Methods: Murine-derived organoids (MDOs) were developed from pancreatic tissue expressing KRASG12D with (Ptf1acreERT/+KRASG12D/+) or without Atf3 (Atf3-/-Ptf1acreERT/+KRASG12D; referred to as APK) expression, and patient-derived organoids (PDOs) were examined for mediators of the UPR. Transcriptomic changes related to ATF3 loss was determined by RNA-sequencing of Ptf1acreERT/+KRASG12D/+ and APK organoids. UPR activation was examined by qRT-PRC in MDOs and PDOs with and without gemcitabine treatment, and related to organoid viability and phenotype. PDOs viability was examined following treatment with gemcitabine +/- UPR inhibitors. Results: RNA-seq analysis of Ptf1acreERT/+KRASG12D/+ and APK MDOs identified drug metabolism cytochrome P450, metabolism of xenobiotics by cytochrome P450, and platinum drug resistance as key pathways affected by the loss of ATF3 suggesting reduced UPR activation impacts drug metabolism in KRASG12D expressing cells. Ptf1acreERT/+KRASG12D/+ and APK MDOs showed a differential response in cell viability and UPR activation to gemcitabine treatment suggesting an importance of ATF3 in gemcitabine resistance. Consistent with this role, treatment of PDOs with gemcitabine resulted in UPR activation in a patient-specific fashion, particularly regarding increased expression of ATF3 and spliced XBP1. In lines showing enhanced UPR activation to gemcitabine, combinatorial treatment with UPR inhibitors showed increased cell death compared to gemcitabine alone. Conclusions: This study shows the UPR and ATF3 are rapidly activated in response to gemcitabine, but in a patient-specific fashion. These results suggest cancer cells activate the UPR to increase resistance to chemotherapies, and a subset of patients may benefit from combined gemcitabine treatment with UPR inhibitors. Since the tumor microenvironment is believed to be a major contributing factor to chemotherapy resistance, future experiments will include the tumor microenvironment interactions and UPR inhibition. Citation Format: Mickenzie B. Martin, Teresa Borello, Fatemeh Mousavi, Nelson Dusetti, Christopher L. Pin. Targeting the unfolded protein response enhances sensitivity to chemotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B090.
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) | 0,005 | 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 ».