Activity of the Fibroblast Growth Factor Receptor Inhibitors Dovitinib (TKI258) and NVP-BGJ398 in Human Endometrial Cancer Cells.

Activity of the Fibroblast Growth Factor Receptor Inhibitors Dovitinib (TKI258) and NVP-BGJ398 in Human Endometrial Cancer Cells.

Mol Cancer Ther. 2013 Feb 26;

Authors: Konecny GE, Kolarova T, O'Brien NA, Winterhoff B, Yang G, Qi J, Qi Z, Venkatesan N, Ayala R, Luo T, Finn RS, Kristof J, Galderisi C, Graus Porta D, Anderson L, Shi MM, Yovine A, Slamon DJ

Abstract
The recent identification of activating fibroblast growth factor receptor 2 (FGFR2) mutations in endometrial cancer (EC) has generated an opportunity for a novel target-based therapy. Here we explore the therapeutic potential of two FGFR inhibitors, the multi-kinase inhibitor dovitinib (TKI258) and the more selective FGFR inhibitor NVP-BGJ398 for the treatment of EC. We examined the effects of both inhibitors on tumor cell growth, FGFR2 signaling, cell cycle and apoptosis using a panel of 20 molecularly characterized human EC cell lines. Anchorage independent growth was studied using soft agar assays. In vivo studies were conducted using EC xenograft models. Cell lines with activating FGFR2 mutations (S252W, N550K) were more sensitive to dovitinib or NVP-BGJ398 when compared to their FGFR2 wild-type counterparts (p=0.073 and p=0.021, respectively). Both agents inhibited FGFR2 signaling, induced cell cycle arrest and significantly increased apoptosis in FGFR2 mutant lines. In vitro, dovitinib and NVP-BGJ398 were both potent at inhibiting cell growth of FGFR2 mutant EC cells but the activity of dovitinib was less restricted to FGFR2 mutant lines when compared to NVP-BGJ398. In vivo, dovitinib and NVP-BGJ398 significantly inhibited the growth of FGFR2 mutated EC xenograft models. In addition, dovitinib showed significant antitumor activity in FGFR2 wild-type EC xenograft models including complete tumor regressions in a long term in vivo study. Dovitinib and NVP-BGJ398 warrant further clinical evaluation in patients with FGFR2 mutated EC. Dovitinib may have antitumor activity in EC beyond FGFR2 mutated cases and may permit greater flexibility in patient selection.

PMID: 23443805 [PubMed - as supplied by publisher]

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