Abstract 5533: Drug tolerance mechanisms in patient-derived xenograft models with <i>epidermal growth factor receptor</i> mutated tumors treated with tyrosine kinase inhibitors
Notice bibliographique
Résumé
Abstract Background and Purpose: Epidermal growth factor receptor (EGFR) mutations on exon 18-21 are oncogenic drivers in 10-60% of patients with lung adenocarcinoma. First and second-generation EGFR tyrosine kinase inhibitors (TKIs) have high efficacy but resistance quickly develops, with 60-70% caused by the emergence of T790M secondary mutation. Osimertinib (osi) is effective against common EGFR mutations as well as T790M, yet most patients eventually also develop resistance. Understanding post-osi resistance mechanisms is a priority research goal. Our goal is to establish large cohort of patient-derived xenograft (PDX) and/or organoid models with EGFR mutations from patients who have progressed on osimertinib and use them to characterize the mechanisms of drug tolerance and resistance. Methods: We have established six PDX models from tumor biopsies and one organoid-derived xenograft (ODX) from a pleural effusion. To assess models response to osi, donor xenograft tumor fragments were implanted into replicate NOD SCID mice and once tumors reached an average tumor volume of 400 mm3, they were randomized into vehicle and osi treatment groups. Osi was dosed at 25mg/kg daily oral gavage for 30 days. Excised tumors were profiled by bulk RNAseq in two models PHLC4547 and 4672. Result: Models were established from tumors of three patients who have progressed on geftinib and osi treatment (PHLC4683Ex19delE746_A750del, PHLC4697L858R/L833V, PHLC4547L858R). Additionally, one progressed on gefitinib PHLC4223L858R and one on afatinib and gefitinib PHLC4192 Ex19delE746_A750del. One progressive on osi PHLC4672L858R/G719 and another patient who progressed on afatinib and osi treatment is PHLC4754L858R/T790M/C797S. PHLC4672 PDX demonstrated drug tolerance and stable tumor size to osi treatment, all other models showed resistance to osi. However, PHLC4547, 4223, 4683 and 4754 showed initial transient tolerance to osi and resistance quickly followed. PHLC4192 and PHLC4697 were completely osi-resistant. Transcriptomic profiling of osi-resistant PHLC4547 revealed no changes in gene expression profile during all three serial passages of osi-treated tumors. However, PHLC4672 with osi-tolerance revealed downregulation of Hallmark gene set enrichment in pathways of G2M checkpoint, E2F targets, mitotic spindle, glycolysis and estrogen response. The EGFR-TKI responses in patients and PDX models showed high concordance among the resistant models. Conclusion: The altered pathways in tolerance model appears to be unique to an osi-stable response compared to an osi-resistance response. PDX models from post-TKI patients may be useful to study the drug resistant mechanism. Citation Format: Arundhathi Arivajiagane, Quan Li, Nhu-An Pham, Ming Li, Katrina Hueniken, Takamasa Koga, Nikolina Radulovich, Ming-Sound Tsao. Drug tolerance mechanisms in patient-derived xenograft models with epidermal growth factor receptor mutated tumors treated with tyrosine kinase inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5533.
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) | 0,002 | 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 ».