title: In Vitro and In Vivo Activity of Lucitanib in FGFR1/2 Amplified or Mutated Cancer Models.
abstract: 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.
authors.affiliation: Laboratory of Molecular Pharmacology, Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156, Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Guffanti
authors.affiliation: Laboratory of Molecular Pharmacology, Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156, Milan, Italy.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Chilà
authors.affiliation: Laboratory of Molecular Pharmacology, Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156, Milan, Italy.
authors.forename: Ezia
authors.initials: E
authors.lastname: Bello
authors.affiliation: Laboratory of Cancer Pharmacology, Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Zucchetti
authors.affiliation: Laboratory of Cancer Pharmacology, Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156, Milan, Italy.
authors.forename: Monique
authors.initials: M
authors.lastname: Zangarini
authors.affiliation: Laboratory of Cancer Pharmacology, Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156, Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Ceriani
authors.affiliation: Laboratory of Cancer Pharmacology, Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156, Milan, Italy.
authors.forename: Mariella
authors.initials: M
authors.lastname: Ferrari
authors.affiliation: Laboratory of Cancer Pharmacology, Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156, Milan, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Lupi
authors.affiliation: Servier Oncology R&D, 50 rue Carnot, 92284 Suresnes, Cedex, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Jacquet-Bescond
authors.affiliation: Servier Oncology R&D, 50 rue Carnot, 92284 Suresnes, Cedex, France.
authors.forename: Mike F
authors.initials: MF
authors.lastname: Burbridge
authors.affiliation: Servier Oncology R&D, 50 rue Carnot, 92284 Suresnes, Cedex, France.
authors.forename: Marie-Jeanne
authors.initials: MJ
authors.lastname: Pierrat
authors.affiliation: Laboratory of Molecular Pharmacology, Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156, Milan, Italy. Electronic address: giovanna.damia@marionegri.it.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Damia
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D009154:Mutation; D009281:Naphthalenes / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C000595232:E-3810; D009281:Naphthalenes; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2