Combinatorial therapy using dovitinib and ICI182.780 (fulvestrant) blocks tumoral activity of endometrial cancer cells.
Mutations in fibroblast growth factor receptor 2 (FGFR2) have been recently described as a molecular-specific feature in endometrial carcinomas and the presence of activated FGFR2 mutations is associated with poor prognosis. For that reason, inhibition of FGFR2 could be a therapeutic target in the treatment of endometriod carcinomas. In this work, we investigated the antitumoral activity of dovitinib (a multiple kinase inhibitor) in human endometrial cancer cell (ECC) lines. 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 that induce cellular senescence. To further investigate the role of dovitinib, we analyzed its effect on estrogen receptor α (ER-α) expression. Surprisingly, we discovered that dovitinib enhances ER-α 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 ER antagonist, fulvestrant (ICI182.780). Combination of dovitinib plus ICI182.780 resulted in a significantly 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 patients with endometrial carcinomas carrying FGFR2 mutations.
Authors' Affiliations: Oncologic Pathology Group, Dept. de Ciències Mèdiques Bàsiques, University of Lleida, Department of Pathology and Molecular Genetics, Hospital Universitari Arnau de Vilanova, Institut de Recerca Biomèdica de Lleida, IRBLleida, Lleida; and Servicio de Oncología Médica, Hospital Arnau de Vilanova, Valencia, Spain.
Nuria
N
Eritja
Mónica
M
Domingo
Maria Alba
MA
Dosil
Cristina
C
Mirantes
Maria
M
Santacana
Joan
J
Valls
Antonio
A
Llombart-Cussac
Xavier
X
Matias-Guiu
Xavier
X
Dolcet
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols; D001562:Benzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D009374:Neoplasms, Experimental; D015363:Quinolones / Q000494:pharmacology* / Q000627:therapeutic use; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D047628:Estrogen Receptor alpha; D015363:Quinolones; D000077267:Fulvestrant; D004958:Estradiol; D051497:Receptor, Fibroblast Growth Factor, Type 2