Combinatorial Therapy Using Dovitinib and ICI182.780 (Fulvestrant) Blocks Tumoral Activity of Endometrial Cancer Cells

Abstract

Mutations in fibroblast growth factor receptor 2 (FGFR2) have been recently described as a molecularspecific 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 a (ER-a) expression. Surprisingly, we discovered that dovitinib enhances ER-a 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. Mol Cancer Ther; 13(4); 776-87. Ó2014 AACR.

A Receptor Tyrosine Kinase Inhibitor, Dovitinib (TKI-258), Enhances BMP-2-Induced Osteoblast Differentiation In Vitro

“…Although dovitinib shows wide ranges of IC50 in many types of cancer cells, this study demonstrated that relatively low concentrations of dovitinib could exert a stimulating effect on the BMP-2-induced osteoblast differentiation of C2C12 cells without significant cytotoxicity. As mentioned in previous reports, dovitinib showed anti-cancer activity through inhibition of FGFRs, PDGFRs, and VEGFRs ( Angevin et al, 2013 ; Eritja et al, 2014 ; Kim et al, 2011 ; Milowsky et al, 2014 ). However, in C2C12 cells, BMP-2 increased the proliferation of C2C12 cells and dovitinib did not exert significant cytotoxicity.…”

“…Dovitinib (TKI-258) was originally developed as a multi-targeted receptor tyrosine kinase (RTK) inhibitor and has a potent inhibitory effect on the activities of the Class III (FLT3/c-Kit), Class IV (FGFR1/3), and Class V (VEGFR1-4) RTKs ( Lopes de Menezes et al, 2005 ; Porta et al, 2015 ). In the previous reports, dovitinib has been used as an anti-cancer agent undergoing preclinical or clinical trials ( Angevin et al, 2013 ; Eritja et al, 2014 ; Kim et al, 2011 ; Milowsky et al, 2014 ).…”

“…Recent reports provide new information about therapeutic applications of anti-cancer agents for the treatment of another disease or synergistic effects with exiting drugs ( Beeharry et al, 2014 ; Bharadwaj et al, 2015 ; Hanusova et al, 2015 ; Pemovska et al, 2015 ; Song et al, 2015 ). Published reports mainly represent that dovitinib exerts anti-cancer activity through inhibition of FGFRs, PDGFRs, and VEGFRs in various types of cancers ( Angevin et al, 2013 ; Eritja et al, 2014 ; Kim et al, 2011 ; Milowsky et al, 2014 ). Targeted therapies, associated with specific types of diseases, have improved in drug discovery and development process.…”

Emerging drugs for endometrial cancer

“…It was discovered that TKI258 enhances ER-a expression in FGFR2-mutant EC cells. Blocking one signal pathway is often not sufficient to cause tumor regression completely; thus, the combination of TKI258, which targets FGFR2, with a selective ER antagonist, fulvestrant, has resulted in a significantly higher inhibition of cell growth than TKI258 treatment alone [88]. Future studies with the combination of target therapies will be guided by strategies to decrease toxicity and increase response rates.…”

Treating gynecologic malignancies with selective estrogen receptor downregulators (SERDs): promise and challenges

“…-mutant cell lines up-regulated ERα and synergized with fulvestrant to inhibit proliferation(149). Additionally, over-expression of ERα was shown to rescue HHUA cells from MEK inhibition(86).…”