We are analyzing https://link.springer.com/article/10.1186/1476-4598-11-75.

Title:
Sensitivity to the MEK inhibitor E6201 in melanoma cells is associated with mutant BRAF and wildtype PTEN status | Molecular Cancer
Description:
Background Melanoma is the most lethal form of skin cancer, but recent advances in molecularly targeted agents against the Ras/Raf/MAPK pathway demonstrate promise as effective therapies. Despite these advances, resistance remains an issue, as illustrated recently by the clinical experience with vemurafenib. Such acquired resistance appears to be the result of parallel pathway activation, such as PI3K, to overcome single-agent inhibition. In this report, we describe the cytotoxicity and anti-tumour activity of the novel MEK inhibitor, E6201, in a broad panel of melanoma cell lines (n = 31) of known mutational profile in vitro and in vivo. We further test the effectiveness of combining E6201 with an inhibitor of PI3K (LY294002) in overcoming resistance in these cell lines. Results The majority of melanoma cell lines were either sensitive (IC50 < 500 nM, 24/31) or hypersensitive (IC50 < 100 nM, 18/31) to E6201. This sensitivity correlated with wildtype PTEN and mutant BRAF status, whereas mutant RAS and PI3K pathway activation were associated with resistance. Although MEK inhibitors predominantly exert a cytostatic effect, E6201 elicited a potent cytocidal effect on most of the sensitive lines studied, as evidenced by Annexin positivity and cell death ELISA. Conversely, E6201 did not induce cell death in the two resistant melanoma cell lines tested. E6201 inhibited xenograft tumour growth in all four melanoma cell lines studied to varying degrees, but a more pronounced anti-tumour effect was observed for cell lines that previously demonstrated a cytocidal response in vitro. In vitro combination studies of E6201 and LY294002 showed synergism in all six melanoma cell lines tested, as defined by a mean combination index < 1. Conclusions Our data demonstrate that E6201 elicits a predominantly cytocidal effect in vitro and in vivo in melanoma cells of diverse mutational background. Resistance to E6201 was associated with disruption of PTEN and activation of downstream PI3K signalling. In keeping with these data we demonstrate that co-inhibition of MAPK and PI3K is effective in overcoming resistance inherent in melanoma.
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Keywords {🔍}

cell, lines, melanoma, pubmed, braf, mek, cells, article, google, scholar, cancer, cas, inhibition, pten, inhibitor, response, treatment, mutant, combination, sensitivity, pik, kinase, resistance, death, status, inhibitors, patients, akt, sensitive, tumour, pathway, activation, vitro, protein, erk, uacc, central, wildtype, growth, signalling, figure, dmso, levels, panel, line, assay, analysis, clinical, mutational, mapk,

Topics {✒️}

ras/raf/mitogen-activated protein kinase mek-igf-1r-mediated feedback loop mitogen-activated protein kinases emerging n-ras/braf/erk data annexin v-fitc–positive cells half-log serial dilution open access article article download pdf 19-tetrahydro-1 h-2-benzoxacyclotetradec ine-1 resorcylic lactone ll-z1640-2 enzyme-linked immunosorbent assay post-relapse tumour biopsies erk-mediated autoregulatory processes cutaneous squamous-cell carcinomas bl tumour-bearing mice genome-wide expression profiling ras-driven lung tumourigenesis ras/raf/mapk pathway pi3k/akt/mtor signalling pronounced anti-tumour effect raf kinase switch caspase-independent cell death half log dilutions observed high igf-1r pi3k/akt/mtor pathway biotek microplate reader overcome single-agent inhibition pi3k/akt/mtor pathways receptor tyrosine kinase[34] braf/ras mutant lines braf-mutant metastatic melanoma single-agent braf inhibition[21] diverse mutational background e6201-resistant melanoma lines braf-mutated melanoma [abstract] e6201-resistant cell lines overcome nras-mediated resistance �kinase switch” allowing selective kinase inhibitors senior research fellowship wild-type braf e6201-induced cell death full size image core pathways activated kinase-dead braf phosphoinositide 3-kinase p110alpha induces growth arrest significant inhibitory effect propidium iodide staining b-raf inhibition

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WebPage:
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         headline:Sensitivity to the MEK inhibitor E6201 in melanoma cells is associated with mutant BRAF and wildtype PTEN status
         description:Melanoma is the most lethal form of skin cancer, but recent advances in molecularly targeted agents against the Ras/Raf/MAPK pathway demonstrate promise as effective therapies. Despite these advances, resistance remains an issue, as illustrated recently by the clinical experience with vemurafenib. Such acquired resistance appears to be the result of parallel pathway activation, such as PI3K, to overcome single-agent inhibition. In this report, we describe the cytotoxicity and anti-tumour activity of the novel MEK inhibitor, E6201, in a broad panel of melanoma cell lines (n = 31) of known mutational profile in vitro and in vivo. We further test the effectiveness of combining E6201 with an inhibitor of PI3K (LY294002) in overcoming resistance in these cell lines. The majority of melanoma cell lines were either sensitive (IC50 < 500 nM, 24/31) or hypersensitive (IC50 < 100 nM, 18/31) to E6201. This sensitivity correlated with wildtype PTEN and mutant BRAF status, whereas mutant RAS and PI3K pathway activation were associated with resistance. Although MEK inhibitors predominantly exert a cytostatic effect, E6201 elicited a potent cytocidal effect on most of the sensitive lines studied, as evidenced by Annexin positivity and cell death ELISA. Conversely, E6201 did not induce cell death in the two resistant melanoma cell lines tested. E6201 inhibited xenograft tumour growth in all four melanoma cell lines studied to varying degrees, but a more pronounced anti-tumour effect was observed for cell lines that previously demonstrated a cytocidal response in vitro. In vitro combination studies of E6201 and LY294002 showed synergism in all six melanoma cell lines tested, as defined by a mean combination index < 1. Our data demonstrate that E6201 elicits a predominantly cytocidal effect in vitro and in vivo in melanoma cells of diverse mutational background. Resistance to E6201 was associated with disruption of PTEN and activation of downstream PI3K signalling. In keeping with these data we demonstrate that co-inhibition of MAPK and PI3K is effective in overcoming resistance inherent in melanoma.
         datePublished:2012-10-05T00:00:00Z
         dateModified:2012-10-05T00:00:00Z
         pageStart:1
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             BRAF
             PTEN
            MEK inhibition
            E6201
            PI3K
            MAPK
            Cancer Research
            Oncology
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ScholarlyArticle:
      headline:Sensitivity to the MEK inhibitor E6201 in melanoma cells is associated with mutant BRAF and wildtype PTEN status
      description:Melanoma is the most lethal form of skin cancer, but recent advances in molecularly targeted agents against the Ras/Raf/MAPK pathway demonstrate promise as effective therapies. Despite these advances, resistance remains an issue, as illustrated recently by the clinical experience with vemurafenib. Such acquired resistance appears to be the result of parallel pathway activation, such as PI3K, to overcome single-agent inhibition. In this report, we describe the cytotoxicity and anti-tumour activity of the novel MEK inhibitor, E6201, in a broad panel of melanoma cell lines (n = 31) of known mutational profile in vitro and in vivo. We further test the effectiveness of combining E6201 with an inhibitor of PI3K (LY294002) in overcoming resistance in these cell lines. The majority of melanoma cell lines were either sensitive (IC50 < 500 nM, 24/31) or hypersensitive (IC50 < 100 nM, 18/31) to E6201. This sensitivity correlated with wildtype PTEN and mutant BRAF status, whereas mutant RAS and PI3K pathway activation were associated with resistance. Although MEK inhibitors predominantly exert a cytostatic effect, E6201 elicited a potent cytocidal effect on most of the sensitive lines studied, as evidenced by Annexin positivity and cell death ELISA. Conversely, E6201 did not induce cell death in the two resistant melanoma cell lines tested. E6201 inhibited xenograft tumour growth in all four melanoma cell lines studied to varying degrees, but a more pronounced anti-tumour effect was observed for cell lines that previously demonstrated a cytocidal response in vitro. In vitro combination studies of E6201 and LY294002 showed synergism in all six melanoma cell lines tested, as defined by a mean combination index < 1. Our data demonstrate that E6201 elicits a predominantly cytocidal effect in vitro and in vivo in melanoma cells of diverse mutational background. Resistance to E6201 was associated with disruption of PTEN and activation of downstream PI3K signalling. In keeping with these data we demonstrate that co-inhibition of MAPK and PI3K is effective in overcoming resistance inherent in melanoma.
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      dateModified:2012-10-05T00:00:00Z
      pageStart:1
      pageEnd:15
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         Melanoma
          BRAF
          PTEN
         MEK inhibition
         E6201
         PI3K
         MAPK
         Cancer Research
         Oncology
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            address:
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               type:PostalAddress
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      name:David C Loch
      affiliation:
            name:Queensland University of Technology
            address:
               name:Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Queensland, Australia
               type:PostalAddress
            type:Organization
      name:Candice L Wellens
      affiliation:
            name:Translational Genomics Research Institute
            address:
               name:Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, USA
               type:PostalAddress
            type:Organization
      name:Andreas Wortmann
      affiliation:
            name:Queensland University of Technology
            address:
               name:Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Queensland, Australia
               type:PostalAddress
            type:Organization
      name:Jiayi Wu
      affiliation:
            name:Eisai Inc.
            address:
               name:Eisai Inc., Andover, USA
               type:PostalAddress
            type:Organization
      name:John Wang
      affiliation:
            name:H3 Biomedicine Inc.
            address:
               name:H3 Biomedicine Inc., Cambridge, USA
               type:PostalAddress
            type:Organization
      name:Kenichi Nomoto
      affiliation:
            name:Eisai Inc.
            address:
               name:Eisai Inc., Andover, USA
               type:PostalAddress
            type:Organization
      name:Pamela M Pollock
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            name:Translational Genomics Research Institute
            address:
               name:Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, USA
               type:PostalAddress
            type:Organization
            name:Queensland University of Technology
            address:
               name:Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Queensland, Australia
               type:PostalAddress
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      email:[email protected]
PostalAddress:
      name:Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, USA
      name:Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Queensland, Australia
      name:Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, USA
      name:Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Queensland, Australia
      name:Eisai Inc., Andover, USA
      name:H3 Biomedicine Inc., Cambridge, USA
      name:Eisai Inc., Andover, USA
      name:Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, USA
      name:Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Queensland, Australia

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