Abstract 3487: Synergy with combined inhibition of upstream EGFR-HER2 and downstream RAF-MEK nodes in breast cancer cells with activating RAS and RAF mutations
Notice bibliographique
Résumé
Abstract Targeted therapies have been developed to target a variety of oncogenic proteins implicated in breast cancer. These include epidermal growth factor receptor (EGFR), epidermal growth factor receptor type-2 (HER-2), as well as RAS, RAF and MEK, which together comprise the mitogen activated protein kinase (MAPK) cascade. Herein, we explored the therapeutic efficacy of tyrosine kinase inhibitors of EGFR and HER-2 by testing these inhibitors on a human metastatic breast cancer cell line MDA-MB-231. We also determined whether inhibiting tyrosine kinase receptors correlated with the activity of downstream nodes such as MEK and ERK. We report that EGFR inhibitors potently inhibited the phosphorylation of EGFR, but had no effect on MEK and ERK activity, which were observed to be constitutively active in this cell line. Interestingly, MEK/ERK insensitivity correlated with cytotoxic resistance of MDA-MB-231 cells to EGFR inhibitor treatment. In contrast, targeting both EGFR and HER-2 with a dual EGFR/HER-2 inhibitor Lapatinib resulted in significantly improved cytotoxic effects and a partial reduction in MEK and ERK activity. In comparison to the effects of Lapatinib, targeting RAF with Sorafenib resulted in almost complete abrogation of MEK/ERK signaling activity and enhanced cytotoxicity. Our results are consistent with earlier reports suggesting that MAPK signaling is required for MDA-MB-231 cell survival, consistent with the reported presence of activating RAS and RAF mutations in this cell line. Our data highlight the role of RAS and RAF mutations in the uncoupling of downstream nodes (MEK and ERK) from upstream receptor activation. Lastly, the MEK inhibitor U1026 fully inhibited ERK activity but exhibited poor cytotoxicity. This suggests that MDA-MB-231 cells may circumvent MEK inhibition through upstream survival pathways mediated by activated RAS or RAF. An apparent synergistic cytotoxic effect was noted when combining Sorafenib and U1026. Cytotoxic synergy was also observed when Sorafenib was combined with Lapatinib. These putative synergistic drug combinations show promise in that they could deliver significant cytotoxic effects with reduced doses. We find there is merit in targeting multiple oncogenic nodes concurrently to promote additional therapeutic benefits. This also shows potential use in targeting a broader variety of cancer cells that harbor constitutive MAPK signaling associated with oncogenic RAS or RAF mutations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3487.
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 distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| 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 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| 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) | 0,000 | 0,000 |
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 tête enseignante, 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 ».