Reference Detail

Ref Type

Journal Article

PMID

(23443805)

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, Porta DG, Anderson L, Shi MM, Yovine A, Slamon DJ

Title

Activity of the fibroblast growth factor receptor inhibitors dovitinib (TKI258) and NVP-BGJ398 in human endometrial cancer cells.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	12	5	2013 May	632-42	Mol Cancer Ther

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
FGFR3	V306I	missense	unknown	FGFR3 V306I lies within Ig-like C2-type domain 3 of the Fgfr3 protein (UniProt.org). V306I has been identified in the scientific literature (PMID: 23443805, PMID: 25384085), but has not been biochemically characterized and therefore, its effect on Fgfr3 protein function is unknown (PubMed, Apr 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FGFR2 mutant	endometrial cancer	sensitive	Infigratinib	Preclinical	Actionable	In a preclinical study, Truseltiq (infigratinib) inhibited the growth of FGFR2-mutated endometrial cancer cells in vitro and in xenograft models (PMID: 23443805).	23443805
FGFR2 act mut	endometrial cancer	sensitive	Dovitinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, both cell lines and cell line xenograft models of endometrial cancer with FGFR2 activating mutations showed greater sensitivity to Dovitinib (TKI258) as compared to FGFR2 wild-type (PMID: 23443805).	23443805