Combinatorial therapy using Dovitinib and ICI182.780 (Fulvestrant) blocks tumoral activity of endometrial cancer cells
Menée sur des lignées cellulaires et des modèles murins de cancer de l'endomètre, cette étude évalue l'activité antitumorale d'un traitement combinant dovetinib et fulvestrant
Mutations in FGFR2 have been recently described as a molecular-specific feature in endometrial carcinomas (EC) and the presence of activated FGR2 mutations is associated with poor prognosis. For that reason, inhibition of FGFR2 could be a therapeutic target in EEC treatment. In this work, we investigated the antitumoral activity of Dovitinib (a multiple kinase inhibitor) in human endometrial cancer cell lines (ECC). We found that Dovitinib caused cell growth arrest, loss of clonogenic growth and cell cycle arrest in FGFR2 mutated ECCs in in vitro and in vivo experiments. Next, we investigated the mechanistic basis of Dovitinib effects. We could determine that Dovitinib modified expression levels of well-known key cell cycle regulatory proteins which induce cellular senescence. To further investigate the role of Dovitinib, we analyzed its effect on estrogen receptor alpha (ERα) expression. Surprisingly, we discovered that Dovitinib enhances ERα expression in FGFR2 mutant ECCs. Because, blocking one signaling pathway is often not sufficient to cause total tumor regression and the effectiveness of individual inhibitors is often short-lived; we examined the impact of targeting FGFR2 with Dovitinib in combination with a selective estrogen receptor antagonist: Fulvestrant (ICI182.780). Combination of Dovitinib plus ICI182.780 resulted in a significant higher inhibition of cell growth than Dovitinib treatment alone. These findings suggest that combinatory therapies using Dovitinib plus ICI182.780 treatment can be truly effective in EC patients carrying FGFR2 mutations.
http://mct.aacrjournals.org/content/early/2014/01/21/1535-7163.MCT-13-0794.abstract