S49076 Is a novel kinase inhibitor of MET, AXL, and FGFR with strong preclinical activity alone and in association with bevacizumab

Mike F. Burbridge, Céline J. Bossard, Carine Saunier, Imre Fejes, Alain Bruno, Stéphane Léonce, Gilles Ferry, Georges Da Violante, Fraņcois Bouzom, Valérie Cattan, Anne Jacquet-Bescond, Paolo M. Comoglio, Brian P. Lockhart, Jean A. Boutin, Alex Cordi, Jean Claude Ortuno, Alain Pierré, John A. Hickman, Francisco H. Cruzalegui, Stéphane Depil

Research output: Contribution to journalArticle

Abstract

Aberrant activity of the receptor tyrosine kinases MET, AXL, and FGFR1/2/3 has been associated with tumor progression in a wide variety of human malignancies, notably in instances of primary or acquired resistance to existing or emerging anticancer therapies. This study describes the preclinical characterization of S49076, a novel, potent inhibitor of MET, AXL/MER, and FGFR1/2/3. S49076 potently blocked cellular phosphorylation of MET, AXL, and FGFRs and inhibited downstream signaling in vitro and in vivo. In cell models, S49076 inhibited the proliferation of MET- and FGFR2-dependent gastric cancer cells, blocked METdriven migration of lung carcinoma cells, and inhibited colony formation of hepatocarcinoma cells expressing FGFR1/2 and AXL. In tumor xenograft models, a good pharmacokinetic/pharmacodynamic relationship for MET and FGFR2 inhibition following oral administration of S49076 was established and correlated well with impact on tumor growth. MET, AXL, and the FGFRs have all been implicated in resistance to VEGF/VEGFR inhibitors such as bevacizumab. Accordingly, combination of S49076 with bevacizumab in colon carcinoma xenograft models led to near total inhibition of tumor growth. Moreover, S49076 alone caused tumor growth arrest in bevacizumab-resistant tumors. On the basis of these preclinical studies showing a favorable and novel pharmacologic profile of S49076, a phase I study is currently underway in patients with advanced solid tumors.

Original languageEnglish
Pages (from-to)1749-1762
Number of pages14
JournalMolecular Cancer Therapeutics
Volume12
Issue number9
DOIs
Publication statusPublished - Sep 2013

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Burbridge, M. F., Bossard, C. J., Saunier, C., Fejes, I., Bruno, A., Léonce, S., Ferry, G., Da Violante, G., Bouzom, F., Cattan, V., Jacquet-Bescond, A., Comoglio, P. M., Lockhart, B. P., Boutin, J. A., Cordi, A., Ortuno, J. C., Pierré, A., Hickman, J. A., Cruzalegui, F. H., & Depil, S. (2013). S49076 Is a novel kinase inhibitor of MET, AXL, and FGFR with strong preclinical activity alone and in association with bevacizumab. Molecular Cancer Therapeutics, 12(9), 1749-1762. https://doi.org/10.1158/1535-7163.MCT-13-0075