Français | English

Agence nationale sanitaire et scientifique en cancérologie

Accueil Nota Bene Cancer V2 Numéro 125 du 28 February 2012 Traitements BREADCRUMB PUBLICATION

Print

Nota Bene Cancer Fiche de publication

The heat shock protein-90 inhibitor XL888 overcomes BRAF inhibitor resistance mediated through diverse mechanisms

Menée in vitro et in vivo, cette étude évalue l'intérêt d'un composé appelé XL888, un inhibiteur de HSP90, en cas d'apparition d'une résistance au vemurafenib dans le traitement d'un mélanome

  • Clinical Cancer Research, sous presse, 2012 (résumé)

Résumé en anglais :
Purpose: The clinical use of BRAF inhibitors is being hampered by the acquisition of drug resistance. This study demonstrates the potential therapeutic utility of the HSP90 inhibitor (XL888) in 6 different models of vemurafenib resistance. Experimental design: The ability of XL888 to inhibit growth and to induce apoptosis and tumor regression of vemurafenib-resistant melanoma cell lines was demonstrated in vitro and in vivo. A novel mass spectrometry-based pharmacodynamic assay was developed to measure intratumoral HSP70 levels following HSP90 inhibition in melanoma cell lines, xenografts and melanoma biopsies. Mechanistic studies were performed to determine the mechanism of XL888-induced apoptosis. Results: XL888 potently inhibited cell growth, induced apoptosis and prevented the growth of vemurafenib resistant melanoma cell lines in 3D cell culture, long-term colony formation assays and human melanoma mouse xenografts. The reversal of the resistance phenotype was associated with the degradation of PDGFR beta, COT, IGFR1, CRAF, ARAF, S6, cyclin D1 and AKT, which in turn led to the nuclear accumulation of FOXO3a, an increase in BIM expression and the downregulation of Mcl-1. In most resistance models, XL888 treatment increased BIM expression, decreased Mcl-1 expression, and induced apoptosis more effectively than dual MEK/PI3K inhibition. Conclusions: HSP90 inhibition may be a highly effective strategy at managing the diverse array of resistance mechanisms being reported to BRAF inhibitors and appears to be more effective at restoring BIM expression and downregulating Mcl-1 expression than combined MEK/PI3K inhibitor therapy.

NBC n° 125 du 28 February 2012

Mots clés : Mélanome; Traitements (Traitements systémiques : découverte et développement)

Recherche de publications

Recherche avancée

Widget

 

Archives

Formulaire d’abonnement

Pour recevoir gratuitement chaque nouveau numéro de Nota Bene Cancer par courriel :

S'abonner

Sources

Pour visualiser l'ensemble des sources alimentant le Nota Bene Cancer :

Accéder au portail des sources du NBC

Foire aux questions

Pour trouver les réponses aux questions que vous vous posez sur Nota Bene Cancer :

Accéder à la F.A.Q.