The recent identification of activating
fibroblast growth factor receptor 2 (FGFR2) mutations in
endometrial cancer has generated an opportunity for a novel target-based
therapy. Here, we explore the therapeutic potential of 2 FGFR inhibitors, the multikinase inhibitor
dovitinib (
TKI258) and the more selective FGFR inhibitor
NVP-BGJ398 for the treatment of
endometrial cancer. 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
endometrial cancer cell lines. Anchorage-independent growth was studied using soft
agar assays. In vivo studies were conducted using
endometrial cancer xenograft models. Cell lines with activating FGFR2 mutations (S252W, N550K) were more sensitive to
dovitinib or
NVP-BGJ398 when compared with 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
endometrial cancer cells, but the activity of
dovitinib was less restricted to FGFR2-mutant lines when compared with
NVP-BGJ398. In vivo,
dovitinib and
NVP-BGJ398 significantly inhibited the growth of FGFR2-mutated
endometrial cancer xenograft models. In addition,
dovitinib showed significant antitumor activity in FGFR2 wild-type
endometrial cancer 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
endometrial cancer.
Dovitinib may have antitumor activity in
endometrial cancer beyond FGFR2-mutated cases and may permit greater flexibility in patient selection.