Reference Detail

Ref Type

Journal Article

PMID

(27988457)

Authors

Guffanti F, Chilà R, Bello E, Zucchetti M, Zangarini M, Ceriani L, Ferrari M, Lupi M, Jacquet-Bescond A, Burbridge MF, Pierrat MJ, Damia G

Title

In Vitro and In Vivo Activity of Lucitanib in FGFR1/2 Amplified or Mutated Cancer Models.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Neoplasia (New York, N.Y.)	19	1	2017 Jan	35-42	Neoplasia

URL

Abstract Text

The fibroblast growth factor receptor (FGFR) pathway has been implicated both as an escape mechanism from anti-angiogenic therapy and as a driver oncogene in different tumor types. Lucitanib is a small molecule inhibitor of vascular endothelial growth factor (VEGF) receptors 1 to 3 (VEGFR1 to 3), platelet derived growth factor α/β (PDGFRα/β) and FGFR1-3 tyrosine kinases and has demonstrated activity in a phase I/II clinical study, with objective RECIST responses in breast cancer patients with FGFR1 or FGF3/4/19 gene amplification, as well as in patients anticipated to benefit from anti-angiogenic agents. We report here the in vitro and in vivo antitumor activity of lucitanib in experimental models with or without FGFR1/2 amplification or mutations. In cell assays, lucitanib potently inhibited the growth of tumor cell lines with amplified FGFR1 or mutated/amplified FGFR2. In all xenograft models studied, lucitanib demonstrated marked tumor growth inhibition due to potent inhibition of angiogenesis. Notably, in two lung cancer models with FGFR1 amplification, the antitumor efficacy was higher, suggesting that the simultaneous inhibition of VEGF and FGF receptors in FGFR1 dependent tumors can be therapeutically advantageous. Similar antitumor activity was observed in FGFR2 wild-type and amplified or mutated xenograft models. Pharmacokinetic studies showed lucitanib plasma concentrations in the micro/sub-micromolar range demonstrated drug accumulation following repeated lucitanib administration.

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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
Lucitanib	Lucitanib	6	5

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Lucitanib		E-3810\|AL3810	DDR1 Inhibitor 10 DDR2 inhibitor 7 FGFR1 Inhibitor 28 FGFR2 Inhibitor 23 PDGFR-alpha Inhibitor 9 VEGFR Inhibitor (Pan) 36	Lucitanib (E-3810) is a multi-tyrosine kinase receptor inhibitor of VEGFR 1-3, DDR2, PDGFRA, and FGFR1-2, that may inhibit tumor angiogenesis, prevent tumor cell proliferation, and induce tumor cell death (PMID: 27988457, PMID: 24696502, PMID: 31619444).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FGFR1 amp	lung carcinoma	sensitive	Lucitanib	Preclinical - Cell line xenograft	Actionable	in a preclinical study, Lucitanib (E-3810) preferentially inhibited growth of FGFR1-amplified lung carcinoma cell lines in culture and in cell line xenograft models (PMID: 27988457).	27988457