ErbB3 expression predicts sensitivity to elisidepsin treatment: inï¿½vitro synergism with cisplatin, paclitaxel and gemcitabine in lung, breast and colon cancer cell lines

Teixidó, Cristina; Arguelaguet, Elisabet; Pons, Berta; Aracil, Miguel; Jimeno, J.; Somoza, Rosa; R, Mares; Cajal, Santiago Ramón y; Hernández‐Losa, Javier

doi:10.3892/ijo.2012.1425

Cited by 12 publications

(8 citation statements)

References 30 publications

(38 reference statements)

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“…MDA-MB-231 cells are a triple negative cell line and do not express estrogen receptor, progesterone receptor or HER2, but do express HER3 [62]. If HER2 is required for HER3 phosphorylation and association with MTK1, then we should not see the association of HER3 with MTK1 in MDA-MB-231 cells.…”

Section: Resultsmentioning

confidence: 99%

HER2/HER3 regulates extracellular acidification and cell migration through MTK1 (MEKK4)

Sollome

Thavathiru

Camenisch

et al. 2014

Cellular Signalling

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Human MAP3K4 (MTK1) functions upstream of mitogen activated protein kinases (MAPKs). In this study we show MTK1 is required for human epidermal growth factor receptor 2/3 (HER2/HER3)-heregulin beta1 (HRG) induced cell migration in MCF-7 breast cancer cells. We demonstrate that HRG stimulation leads to association of MTK1 with activated HER3 in MCF-7 and T-47D breast cancer cells. Activated HER3 association with MTK1 is dependent on HER2 activation and is decreased by pre-treatment with the HER2 inhibitor, lapatinib. Moreover, we also identify the actin interacting region (AIR) on MTK1. Disruption of actin cytoskeletal polymerization with cytochalasin D inhibited HRG induced MTK1/HER3 association. Additionally, HRG stimulation leads to extracellular acidification that is independent of cellular proliferation. HRG induced extracellular acidification is significantly inhibited when MTK1 is knocked down in MCF-7 cells. Similarly, pre-treatment with lapatinib significantly decreased HRG induced extracellular acidification. Extracellular acidification is linked with cancer cell migration. We performed scratch assays that show HRG induced cell migration in MCF-7 cells. Knockdown of MTK1 significantly inhibited HRG induced cell migration. Furthermore, pre-treatment with lapatinib also significantly decreased cell migration. Cell migration is required for cancer cell metastasis, which is the major cause of cancer patient mortality. We identify MTK1 in the HER2/HER3-HRG mediated extracellular acidification and cell migration pathway in breast cancer cells.

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Section: Resultsmentioning

confidence: 99%

HER2/HER3 regulates extracellular acidification and cell migration through MTK1 (MEKK4)

Sollome

Thavathiru

Camenisch

et al. 2014

Cellular Signalling

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“…Preclinically, elisidepsin showed antiproliferative activity against a broad spectrum of tumor types [5]. Additionally, elisidepsin has been found to have synergistic effects when combined with several different conventional chemotherapeutic agents and tyrosine kinase inhibitors in cell lines and mouse xenograft models most likely due to its unique mechanism of action [6,7]. In clinical trials, elisidepsin has been shown to have a low toxicity profile [8,9,10,11] and preliminary assessment of its clinical efficacy showed interesting results in different solid tumors [8,9,10,11,12].…”

Section: Introductionmentioning

confidence: 99%

“…Although ErbB proteins have been implicated as the target of elisidepsin based on weak correlations between the drug’s efficiency and ErbB protein expression levels [6,7,13], we have refuted this hypothesis by showing that the expression of ErbB1, ErbB2 or ErbB3 proteins have no influence on the sensitivity of cell lines to elisidepsin [14]. According to the most widely accepted view the primary mechanism of action of elisidepsin involves a direct hit on the membrane by binding to lipid rafts [5,14].…”

Section: Introductionmentioning

confidence: 99%

Hypoxia Reduces the Efficiency of Elisidepsin by Inhibiting Hydroxylation and Altering the Structure of Lipid Rafts

et al. 2013

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The mechanism of action of elisidepsin (PM02734, Irvalec®) is assumed to involve membrane permeabilization via attacking lipid rafts and hydroxylated lipids. Here we investigate the role of hypoxia in the mechanism of action of elisidepsin. Culturing under hypoxic conditions increased the half-maximal inhibitory concentration and decreased the drug’s binding to almost all cell lines which was reversed by incubation of cells with 2-hydroxy palmitic acid. The expression of fatty acid 2-hydroxylase was strongly correlated with the efficiency of the drug and inversely correlated with the effect of hypoxia. Number and brightness analysis and fluorescence anisotropy experiments showed that hypoxia decreased the clustering of lipid rafts and altered the structure of the plasma membrane. Although the binding of elisidepsin to the membrane is non-cooperative, its membrane permeabilizing effect is characterized by a Hill coefficient of ~3.3. The latter finding is in agreement with elisidepsin-induced clusters of lipid raft-anchored GFP visualized by confocal microscopy. We propose that the concentration of elisidepsin needs to reach a critical level in the membrane above which elisidepsin induces the disruption of the cell membrane. Testing for tumor hypoxia or the density of hydroxylated lipids could be an interesting strategy to increase the efficiency of elisidepsin.

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“…In our study, cell lines harboring mutated KRAS were less sensitive to elisidepsin, suggesting that KRAS may be regarded as a negative predictive factor of response to the drug. Interestingly, reviewing previous work by Teixido and colleagues, we found that the author characterized MiaPaCa2, Panc1, HCT116 and HOP62 cell lines as being the most resistant cell lines in their panel [7]. These cells are known to carry activated KRAS mutation, whereas BxPC3, which is a pancreatic cell line with wild type KRAS, was extremely sensitive to the drug.…”

Section: Discussionmentioning

confidence: 87%

“…As for KF, recent studies have shown a correlation between elisidepsin sensitivity and the expression of the ErbB3 receptor in a panel of NSCLC and other cell lines [6,7]. Elisidepsin exposure was shown to induce downregulation of ErbB3 protein expression in most cell lines.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2013

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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.

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ErbB3 expression predicts sensitivity to elisidepsin treatment: inï¿½vitro synergism with cisplatin, paclitaxel and gemcitabine in lung, breast and colon cancer cell lines

Cited by 12 publications

References 30 publications

HER2/HER3 regulates extracellular acidification and cell migration through MTK1 (MEKK4)

HER2/HER3 regulates extracellular acidification and cell migration through MTK1 (MEKK4)

Hypoxia Reduces the Efficiency of Elisidepsin by Inhibiting Hydroxylation and Altering the Structure of Lipid Rafts

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

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