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Mar. Drugs 2013, 11(3), 944-959;

Predictive Factors of Sensitivity to Elisidepsin, a Novel Kahalalide F-Derived Marine Compound

AAREC Filia Research, 1, Paul Verlaine, Boulogne Billancourt 92100, France
INSERM U728 and Departments of Medical Oncology, Beaujon University Hospital (AP-HP-Paris 7 Diderot), 100, bd General Leclerc, Clichy 92110, France
Laboratory of Molecular Genetics, Beaujon University Hospital, Paris 7 Diderot, 100, bd General Leclerc, Clichy 92110, France
Cell Biology Department, PharmaMar, Avda de los Reyes 1, Pol. Ind. La Mina, Colmenar Viejo (Madrid) 28770, Spain
Author to whom correspondence should be addressed.
Received: 28 December 2012 / Revised: 21 January 2013 / Accepted: 22 February 2013 / Published: 20 March 2013
(This article belongs to the Special Issue Marine Compounds as Protein Kinase Inhibitors)
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Elisidepsin (PM02734, Irvalec®) is a synthetic marine-derived cyclic peptide of the Kahalalide F family currently in phase II clinical development. Elisidepsin was shown to induce rapid oncosis in ErbB3-expressing cells. Other predictive factors of elisidepsin sensitivity remained unknown. A panel of 23 cancer cell lines of different origin was assessed for elisidepsin cytotoxicity and correlated with mutational state, mRNA and protein expression of selected genes. Elisidepsin showed potent and broad cytotoxic effects in our cancer cell line panel, being active at concentrations ranging from 0.4 to 2 μM that may be relevant for clinical settings. We have shown that elisidepsin is more active in cells harboring epithelial phenotype with high E-cadherin and low vimentin expression. In addition, high ErbB3 and Muc1 expression was correlated with sensitivity to elisidepsin, whereas the presence of KRAS activating mutations was associated with resistance. In DU-PM cells with acquired resistance to elisidepsin, ErbB3 expression was decreased, while Bcl2 was increased. DU-PM cells displayed higher sensitivity to ErbB1-inhibitors suggesting possible cross-talk of ErbB1 and ErbB3 signaling pathways. Combinations of elisidepsin with lapatinib and several chemotherapies including 5-FU and oxaliplatin resulted in synergistic effects that offer the potential of clinical use of elisidepsin in combination settings. View Full-Text
Keywords: Irvalec; oncosis; E-cadherin; ErbB3 Irvalec; oncosis; E-cadherin; ErbB3

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Serova, M.; de Gramont, A.; Bieche, I.; Riveiro, M.E.; Galmarini, C.M.; Aracil, M.; Jimeno, J.; Faivre, S.; Raymond, E. Predictive Factors of Sensitivity to Elisidepsin, a Novel Kahalalide F-Derived Marine Compound. Mar. Drugs 2013, 11, 944-959.

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