Abstract 4469: Combating lapatinib resistance of HER2 positive breast cancer cells by combined inhibition of mTOR and autophagy.
Notice bibliographique
Résumé
Abstract Lapatinib, a dual epidermal growth factor receptor 1 (EGFR) and human epidermal growth factor receptor 2 (HER2) tyrosine kinase inhibitor, has emerged as a second line therapy for breast cancer patients who relapse following trastuzumab and is being tested in clinical trials as a single agent or in combination settings. However, like trastuzumab, development of resistance to lapatinib presents a problem in the clinic. A number of mechanisms have been proposed to explain both intrinsic and acquired resistance to HER2 targeted therapies, one of which involves upregulation of signaling through the PI3K/Akt/mTOR pathway. Thus, we tested if resistance to lapatinib can be overcome by drug combinations that achieve control over both HER2 and mTOR signaling. Our results showed that lapatinib in combination with KU-0063794 (KU), a catalytic mTOR kinase inhibitor that blocks mTORC1 and mTORC2 signaling, had a synergistic effect on cell growth inhibition in both lapatinib sensitive and resistant cell lines. The combination of these two inhibitors achieved a more effective blockade of signaling downstream of mTORC1 than either inhibitor alone as measured by decreased phosphorylation of 4E-BP1 and S6. Due to links between mTOR and autophagy, we also examined how these inhibitors may be influencing the autophagy process. To measure autophagic flux we used a combination of immunoblotting against LC3-II, a marker of autophagic vesicles, and p62, an adaptor protein that is selectively degraded upon autophagosome-lysosome fusion. Both lapatinib and KU induced expression of LC3-II and reduced p62 levels, together suggesting that these inhibitors increase autophagic flux. Using monodansylcadaverine (MDC) to label autophagic vesicles, we found that the combination of lapatinib and KU increased the total MDC-positive vesicle area per cell to a greater extent than an equimolar concentration of either compound alone. Since autophagy is considered a survival mechanism, we tested whether impairing this process with hydroxychloroquine (HCQ), a compound that blocks autophagic flux, may augment activity of the lapatinib and KU combination. Cell viability as assessed by an alamar blue assay showed that inhibition of cell growth by lapatinib and KU was further enhanced by addition of HCQ in JIMT-1 and MDA-MB-361 cells. In addition, live cell imaging of caspase-3/7 activation in MDA-MB-361 showed that HCQ increased the number of apoptotic cells induced by the lapatinib and KU combination from 32% to 78% at the highest dose tested. The efficacy of this triple combination is currently being tested in xenograft models. In conclusion, lapatinib resistance of two HER2 overexpressing cell lines can be effectively reversed by treating cells with a combination of lapatinib, a catalytic mTOR inhibitor, and an autophagy inhibitor. This may be a feasible treatment strategy for relapsed or metastatic HER2 positive breast cancer. Citation Format: Sherry A. Weppler, Wieslawa H. Dragowska, Guido J. Kierkels, Jenna Rawji, Sharon M. Gorski, Marcel B. Bally. Combating lapatinib resistance of HER2 positive breast cancer cells by combined inhibition of mTOR and autophagy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4469. doi:10.1158/1538-7445.AM2013-4469
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) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 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 ».