Abstract
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.
Highlights
Natural products have been a common source of anticancer drugs
We characterized the cytotoxicity of elisidepsin in a panel of human cancer cell lines and, to improve its potential use in clinic, we described potential predictive molecular markers of sensitivity and resistance
To gain insight into the role of epithelial/mesenchymal cell differentiation in elisidepsin antiproliferative activity, we studied elisidepsin effects in two different models inducible for epithelial-to-mesenchymal transition (EMT): DLD-1TR21-hSnail, which contain an inducible SNAIL
Summary
Natural products have been a common source of anticancer drugs. Kahalalide F (KF) belongs to a family of natural depsipeptides that were first isolated from the Hawaiian herbivorous marine sacoglossan mollusk Elysia rufescens (Plakobranchidae) and later from its green algal diet of Bryopsis pennata (Bryopsidaceae) [1]. The above results, associated with the observation by Varadi and colleagues that elisidepsin induced characteristic changes in the organization of the plasma membrane, suggested to the authors that the observed modification in the ErbB receptors signaling pathways were only the consequences of the initial cell membrane alterations [8]. They showed that some changes were specific to ErbB3, such as the increased sensitivity to an ErbB3 conformation-sensitive antibody. We characterized the cytotoxicity of elisidepsin in a panel of human cancer cell lines and, to improve its potential use in clinic, we described potential predictive molecular markers of sensitivity and resistance
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