AEBP1 upregulation confers acquired resistance to BRAF (V600E) inhibition in melanoma View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2013-11-07

AUTHORS

W Hu, L Jin, C C Jiang, G V Long, R A Scolyer, Q Wu, X D Zhang, Y Mei, M Wu

ABSTRACT

An activating BRAF (V600E) kinase mutation occurs in approximately half of melanomas. Recent clinical studies have demonstrated that vemurafenib (PLX4032) and dabrafenib, potent and selective inhibitors of mutant v-raf murine sarcoma viral oncogene homolog B1 (BRAF), exhibit remarkable activities in patients with V600 BRAF mutant melanomas. However, acquired drug resistance invariably develops after the initial treatment. Identification of acquired resistance mechanisms may inform the development of new therapies that elicit long-term responses of melanomas to BRAF inhibitors. Here we report that increased expression of AEBP1 (adipocyte enhancer-binding protein 1) confers acquired resistance to BRAF inhibition in melanoma. AEBP1 is shown to be highly upregulated in PLX4032-resistant melanoma cells because of the hyperactivation of the PI3K/Akt-cAMP response element-binding protein (CREB) signaling pathway. This upregulates AEBP1 expression and thus leads to the activation of NF-κB via accelerating IκBa degradation. In addition, inhibition of the PI3K/Akt-CREB-AEBP1-NF-κB pathway greatly reverses the PLX4032-resistant phenotype of melanoma cells. Furthermore, increased expression of AEBP1 is validated in post-treatment tumors in patients with acquired resistance to BRAF inhibitor. Therefore, these results reveal a novel PI3K/Akt-CREB-AEBP1-NF-κB pathway whose activation contributes to acquired resistance to BRAF inhibition, and suggest that this pathway, particularly AEBP1, may represent a novel therapeutic target for treating BRAF inhibitor-resistant melanoma. More... »

PAGES

e914-e914

Journal

TITLE

Cell Death & Disease

ISSUE

11

VOLUME

4

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/cddis.2013.441

DOI

http://dx.doi.org/10.1038/cddis.2013.441

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1031496643

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/24201813


Indexing Status Check whether this publication has been indexed by Scopus and Web Of Science using the SN Indexing Status Tool
Incoming Citations Browse incoming citations for this publication using opencitations.net

JSON-LD is the canonical representation for SciGraph data.

TIP: You can open this SciGraph record using an external JSON-LD service: JSON-LD Playground Google SDTT

[
  {
    "@context": "https://springernature.github.io/scigraph/jsonld/sgcontext.json", 
    "about": [
      {
        "id": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/06", 
        "inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/", 
        "name": "Biological Sciences", 
        "type": "DefinedTerm"
      }, 
      {
        "id": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/11", 
        "inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/", 
        "name": "Medical and Health Sciences", 
        "type": "DefinedTerm"
      }, 
      {
        "id": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/0601", 
        "inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/", 
        "name": "Biochemistry and Cell Biology", 
        "type": "DefinedTerm"
      }, 
      {
        "id": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/1112", 
        "inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/", 
        "name": "Oncology and Carcinogenesis", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Animals", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "CREB-Binding Protein", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Carboxypeptidases", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Cell Line, Tumor", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Chromatin Immunoprecipitation", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Drug Resistance, Neoplasm", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Humans", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "In Vitro Techniques", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Indoles", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Lentivirus", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Melanoma", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Mice", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Mice, Nude", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "NF-kappa B", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Proto-Oncogene Proteins B-raf", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Proto-Oncogene Proteins c-akt", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "RNA, Small Interfering", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Repressor Proteins", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Reverse Transcriptase Polymerase Chain Reaction", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Signal Transduction", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Sulfonamides", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Vemurafenib", 
        "type": "DefinedTerm"
      }
    ], 
    "author": [
      {
        "affiliation": {
          "alternateName": "Department of Immunology, Anhui Medical University, Anhui, China", 
          "id": "http://www.grid.ac/institutes/grid.186775.a", 
          "name": [
            "Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Anhui, China", 
            "Department of Immunology, Anhui Medical University, Anhui, China"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Hu", 
        "givenName": "W", 
        "id": "sg:person.01362755716.08", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01362755716.08"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Anhui, China", 
          "id": "http://www.grid.ac/institutes/grid.59053.3a", 
          "name": [
            "Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Anhui, China"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Jin", 
        "givenName": "L", 
        "id": "sg:person.01246527316.15", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01246527316.15"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "School of Biomedical Science and Pharmacy, University of Newcastle, Newcastle, NSW, Australia", 
          "id": "http://www.grid.ac/institutes/grid.266842.c", 
          "name": [
            "School of Biomedical Science and Pharmacy, University of Newcastle, Newcastle, NSW, Australia"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Jiang", 
        "givenName": "C C", 
        "id": "sg:person.0617201523.26", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0617201523.26"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Melanoma Institute Australia and Westmead Institute for Cancer Research, University of Sydney, Sydney, NSW, Australia", 
          "id": "http://www.grid.ac/institutes/grid.452919.2", 
          "name": [
            "Melanoma Institute Australia and Westmead Institute for Cancer Research, University of Sydney, Sydney, NSW, Australia"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Long", 
        "givenName": "G V", 
        "id": "sg:person.0664165567.96", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0664165567.96"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Discipline of Pathology, University of Sydney; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital; Melanoma Institute Australia, Sydney, NSW, Australia", 
          "id": "http://www.grid.ac/institutes/grid.1013.3", 
          "name": [
            "Discipline of Pathology, University of Sydney; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital; Melanoma Institute Australia, Sydney, NSW, Australia"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Scolyer", 
        "givenName": "R A", 
        "id": "sg:person.01276020470.05", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01276020470.05"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "State Key Laboratory of Cellular Stress Biology, School of Life sciences, Xiamen University, Xiamen, China", 
          "id": "http://www.grid.ac/institutes/grid.12955.3a", 
          "name": [
            "State Key Laboratory of Cellular Stress Biology, School of Life sciences, Xiamen University, Xiamen, China"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Wu", 
        "givenName": "Q", 
        "id": "sg:person.01154115445.79", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01154115445.79"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "School of Biomedical Science and Pharmacy, University of Newcastle, Newcastle, NSW, Australia", 
          "id": "http://www.grid.ac/institutes/grid.266842.c", 
          "name": [
            "School of Biomedical Science and Pharmacy, University of Newcastle, Newcastle, NSW, Australia"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Zhang", 
        "givenName": "X D", 
        "id": "sg:person.01210116316.18", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01210116316.18"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Anhui, China", 
          "id": "http://www.grid.ac/institutes/grid.59053.3a", 
          "name": [
            "Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Anhui, China"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Mei", 
        "givenName": "Y", 
        "id": "sg:person.0670037002.47", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0670037002.47"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Anhui, China", 
          "id": "http://www.grid.ac/institutes/grid.59053.3a", 
          "name": [
            "Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Anhui, China"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Wu", 
        "givenName": "M", 
        "id": "sg:person.01245131545.13", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01245131545.13"
        ], 
        "type": "Person"
      }
    ], 
    "citation": [
      {
        "id": "sg:pub.10.1038/43466", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1049854869", 
          "https://doi.org/10.1038/43466"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/nature11249", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1006053948", 
          "https://doi.org/10.1038/nature11249"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/nature00766", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1023536940", 
          "https://doi.org/10.1038/nature00766"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/nature10662", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1028208693", 
          "https://doi.org/10.1038/nature10662"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/ncomms1727", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1011476380", 
          "https://doi.org/10.1038/ncomms1727"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/onc.2011.424", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1052459700", 
          "https://doi.org/10.1038/onc.2011.424"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/378092a0", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1014005971", 
          "https://doi.org/10.1038/378092a0"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/nature09626", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1035733152", 
          "https://doi.org/10.1038/nature09626"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/nature09627", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1005907434", 
          "https://doi.org/10.1038/nature09627"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/nature10868", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1038374700", 
          "https://doi.org/10.1038/nature10868"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/nature11183", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1053677952", 
          "https://doi.org/10.1038/nature11183"
        ], 
        "type": "CreativeWork"
      }
    ], 
    "datePublished": "2013-11-07", 
    "datePublishedReg": "2013-11-07", 
    "description": "An activating BRAF (V600E) kinase mutation occurs in approximately half of melanomas. Recent clinical studies have demonstrated that vemurafenib (PLX4032) and dabrafenib, potent and selective inhibitors of mutant v-raf murine sarcoma viral oncogene homolog B1 (BRAF), exhibit remarkable activities in patients with V600 BRAF mutant melanomas. However, acquired drug resistance invariably develops after the initial treatment. Identification of acquired resistance mechanisms may inform the development of new therapies that elicit long-term responses of melanomas to BRAF inhibitors. Here we report that increased expression of AEBP1 (adipocyte enhancer-binding protein 1) confers acquired resistance to BRAF inhibition in melanoma. AEBP1 is shown to be highly upregulated in PLX4032-resistant melanoma cells because of the hyperactivation of the PI3K/Akt-cAMP response element-binding protein (CREB) signaling pathway. This upregulates AEBP1 expression and thus leads to the activation of NF-\u03baB via accelerating I\u03baBa degradation. In addition, inhibition of the PI3K/Akt-CREB-AEBP1-NF-\u03baB pathway greatly reverses the PLX4032-resistant phenotype of melanoma cells. Furthermore, increased expression of AEBP1 is validated in post-treatment tumors in patients with acquired resistance to BRAF inhibitor. Therefore, these results reveal a novel PI3K/Akt-CREB-AEBP1-NF-\u03baB pathway whose activation contributes to acquired resistance to BRAF inhibition, and suggest that this pathway, particularly AEBP1, may represent a novel therapeutic target for treating BRAF inhibitor-resistant melanoma.", 
    "genre": "article", 
    "id": "sg:pub.10.1038/cddis.2013.441", 
    "isAccessibleForFree": true, 
    "isFundedItemOf": [
      {
        "id": "sg:grant.6979921", 
        "type": "MonetaryGrant"
      }
    ], 
    "isPartOf": [
      {
        "id": "sg:journal.1042939", 
        "issn": [
          "2041-4889"
        ], 
        "name": "Cell Death & Disease", 
        "publisher": "Springer Nature", 
        "type": "Periodical"
      }, 
      {
        "issueNumber": "11", 
        "type": "PublicationIssue"
      }, 
      {
        "type": "PublicationVolume", 
        "volumeNumber": "4"
      }
    ], 
    "keywords": [
      "BRAF inhibition", 
      "BRAF inhibitors", 
      "PLX4032-resistant melanoma cells", 
      "Akt-CREB", 
      "BRAF inhibitor-resistant melanoma", 
      "melanoma cells", 
      "post-treatment tumors", 
      "recent clinical studies", 
      "v-raf murine sarcoma viral oncogene homolog B1", 
      "BRAF-mutant melanoma", 
      "novel therapeutic target", 
      "expression of AEBP1", 
      "response element-binding protein", 
      "BRAF kinase mutations", 
      "I\u03baBa degradation", 
      "initial treatment", 
      "half of melanomas", 
      "clinical studies", 
      "mutant melanoma", 
      "new therapies", 
      "NF-\u03baB", 
      "therapeutic target", 
      "element-binding protein", 
      "AEBP1 expression", 
      "melanoma", 
      "drug resistance", 
      "kinase mutations", 
      "selective inhibitor", 
      "patients", 
      "long-term response", 
      "inhibition", 
      "inhibitors", 
      "resistance mechanisms", 
      "AEBP1", 
      "pathway", 
      "activation", 
      "expression", 
      "cells", 
      "dabrafenib", 
      "therapy", 
      "vemurafenib", 
      "tumors", 
      "confers", 
      "hyperactivation", 
      "resistance", 
      "treatment", 
      "remarkable activity", 
      "phenotype", 
      "mutations", 
      "B1", 
      "response", 
      "target", 
      "half", 
      "activity", 
      "protein", 
      "study", 
      "mechanism", 
      "identification", 
      "addition", 
      "development", 
      "results", 
      "degradation"
    ], 
    "name": "AEBP1 upregulation confers acquired resistance to BRAF (V600E) inhibition in melanoma", 
    "pagination": "e914-e914", 
    "productId": [
      {
        "name": "dimensions_id", 
        "type": "PropertyValue", 
        "value": [
          "pub.1031496643"
        ]
      }, 
      {
        "name": "doi", 
        "type": "PropertyValue", 
        "value": [
          "10.1038/cddis.2013.441"
        ]
      }, 
      {
        "name": "pubmed_id", 
        "type": "PropertyValue", 
        "value": [
          "24201813"
        ]
      }
    ], 
    "sameAs": [
      "https://doi.org/10.1038/cddis.2013.441", 
      "https://app.dimensions.ai/details/publication/pub.1031496643"
    ], 
    "sdDataset": "articles", 
    "sdDatePublished": "2022-10-01T06:38", 
    "sdLicense": "https://scigraph.springernature.com/explorer/license/", 
    "sdPublisher": {
      "name": "Springer Nature - SN SciGraph project", 
      "type": "Organization"
    }, 
    "sdSource": "s3://com-springernature-scigraph/baseset/20221001/entities/gbq_results/article/article_596.jsonl", 
    "type": "ScholarlyArticle", 
    "url": "https://doi.org/10.1038/cddis.2013.441"
  }
]
 

Download the RDF metadata as:  json-ld nt turtle xml License info

HOW TO GET THIS DATA PROGRAMMATICALLY:

JSON-LD is a popular format for linked data which is fully compatible with JSON.

curl -H 'Accept: application/ld+json' 'https://scigraph.springernature.com/pub.10.1038/cddis.2013.441'

N-Triples is a line-based linked data format ideal for batch operations.

curl -H 'Accept: application/n-triples' 'https://scigraph.springernature.com/pub.10.1038/cddis.2013.441'

Turtle is a human-readable linked data format.

curl -H 'Accept: text/turtle' 'https://scigraph.springernature.com/pub.10.1038/cddis.2013.441'

RDF/XML is a standard XML format for linked data.

curl -H 'Accept: application/rdf+xml' 'https://scigraph.springernature.com/pub.10.1038/cddis.2013.441'


 

This table displays all metadata directly associated to this object as RDF triples.

336 TRIPLES      21 PREDICATES      122 URIs      101 LITERALS      29 BLANK NODES

Subject Predicate Object
1 sg:pub.10.1038/cddis.2013.441 schema:about N20c099587eaa4956b23dc4ea06907178
2 N261f8efcea90484ba8e8c37643ab8c91
3 N28f9db32e07848799b8f141435f88207
4 N39fca23ab92c4726bbb12272cf863576
5 N3aa3ebefcf4840168fb97c2a8a55d96c
6 N3abf8682c8f143ed9499966c3d26f807
7 N40b50499abb84f5080724459d0e5c473
8 N4d67c3cd48c341fabd64648dba7b736e
9 N4f7f1ed906e049e79a612b8fef70d8b6
10 N59128692901b487cabf53b2501ff9b81
11 N62243a9d010449448a92d4ca7f9a448d
12 N64688cf11a91424fb249fbf2720a9fd7
13 N6ce6e9ca0ad74a21825c6b36e8db3042
14 N7f7330600132487ca81408e2c66e1c6d
15 N85f851cd0391496591abb638e6799cd7
16 N9e18f42a2d9542559e6513ada938184a
17 Nb289c52af2824486b7391a717a416d23
18 Nb6c3db903be14a0e86e22aedfa6391f6
19 Nb7ec49ff11cd412da1f71872848d6049
20 Ndbbd833950644a3586969dd5ae326fb8
21 Ndf503c458a5447a7b148a01d8f260f08
22 Ne4ad37f4e6104716b1504c53c3d3ecc6
23 anzsrc-for:06
24 anzsrc-for:0601
25 anzsrc-for:11
26 anzsrc-for:1112
27 schema:author N655c33b9449e4cc9b4434ec28a3c80f3
28 schema:citation sg:pub.10.1038/378092a0
29 sg:pub.10.1038/43466
30 sg:pub.10.1038/nature00766
31 sg:pub.10.1038/nature09626
32 sg:pub.10.1038/nature09627
33 sg:pub.10.1038/nature10662
34 sg:pub.10.1038/nature10868
35 sg:pub.10.1038/nature11183
36 sg:pub.10.1038/nature11249
37 sg:pub.10.1038/ncomms1727
38 sg:pub.10.1038/onc.2011.424
39 schema:datePublished 2013-11-07
40 schema:datePublishedReg 2013-11-07
41 schema:description An activating BRAF (V600E) kinase mutation occurs in approximately half of melanomas. Recent clinical studies have demonstrated that vemurafenib (PLX4032) and dabrafenib, potent and selective inhibitors of mutant v-raf murine sarcoma viral oncogene homolog B1 (BRAF), exhibit remarkable activities in patients with V600 BRAF mutant melanomas. However, acquired drug resistance invariably develops after the initial treatment. Identification of acquired resistance mechanisms may inform the development of new therapies that elicit long-term responses of melanomas to BRAF inhibitors. Here we report that increased expression of AEBP1 (adipocyte enhancer-binding protein 1) confers acquired resistance to BRAF inhibition in melanoma. AEBP1 is shown to be highly upregulated in PLX4032-resistant melanoma cells because of the hyperactivation of the PI3K/Akt-cAMP response element-binding protein (CREB) signaling pathway. This upregulates AEBP1 expression and thus leads to the activation of NF-κB via accelerating IκBa degradation. In addition, inhibition of the PI3K/Akt-CREB-AEBP1-NF-κB pathway greatly reverses the PLX4032-resistant phenotype of melanoma cells. Furthermore, increased expression of AEBP1 is validated in post-treatment tumors in patients with acquired resistance to BRAF inhibitor. Therefore, these results reveal a novel PI3K/Akt-CREB-AEBP1-NF-κB pathway whose activation contributes to acquired resistance to BRAF inhibition, and suggest that this pathway, particularly AEBP1, may represent a novel therapeutic target for treating BRAF inhibitor-resistant melanoma.
42 schema:genre article
43 schema:isAccessibleForFree true
44 schema:isPartOf N1e790e9a61a440c984b543da35d5b252
45 N5b258162b0a942bfadd94e87c8085d03
46 sg:journal.1042939
47 schema:keywords AEBP1
48 AEBP1 expression
49 Akt-CREB
50 B1
51 BRAF inhibition
52 BRAF inhibitor-resistant melanoma
53 BRAF inhibitors
54 BRAF kinase mutations
55 BRAF-mutant melanoma
56 IκBa degradation
57 NF-κB
58 PLX4032-resistant melanoma cells
59 activation
60 activity
61 addition
62 cells
63 clinical studies
64 confers
65 dabrafenib
66 degradation
67 development
68 drug resistance
69 element-binding protein
70 expression
71 expression of AEBP1
72 half
73 half of melanomas
74 hyperactivation
75 identification
76 inhibition
77 inhibitors
78 initial treatment
79 kinase mutations
80 long-term response
81 mechanism
82 melanoma
83 melanoma cells
84 mutant melanoma
85 mutations
86 new therapies
87 novel therapeutic target
88 pathway
89 patients
90 phenotype
91 post-treatment tumors
92 protein
93 recent clinical studies
94 remarkable activity
95 resistance
96 resistance mechanisms
97 response
98 response element-binding protein
99 results
100 selective inhibitor
101 study
102 target
103 therapeutic target
104 therapy
105 treatment
106 tumors
107 v-raf murine sarcoma viral oncogene homolog B1
108 vemurafenib
109 schema:name AEBP1 upregulation confers acquired resistance to BRAF (V600E) inhibition in melanoma
110 schema:pagination e914-e914
111 schema:productId N12a503715bcc43938c320d7c1880cbbd
112 N5259caf10480403f9d70e75c50f01681
113 Nfa59b192912b434e8d4a5c4c6c42445f
114 schema:sameAs https://app.dimensions.ai/details/publication/pub.1031496643
115 https://doi.org/10.1038/cddis.2013.441
116 schema:sdDatePublished 2022-10-01T06:38
117 schema:sdLicense https://scigraph.springernature.com/explorer/license/
118 schema:sdPublisher N1e0efc7bafa14d11beefeffd23782e04
119 schema:url https://doi.org/10.1038/cddis.2013.441
120 sgo:license sg:explorer/license/
121 sgo:sdDataset articles
122 rdf:type schema:ScholarlyArticle
123 N12a503715bcc43938c320d7c1880cbbd schema:name doi
124 schema:value 10.1038/cddis.2013.441
125 rdf:type schema:PropertyValue
126 N1cab3baa5b7d47c5ab00589eeffc130e rdf:first sg:person.0670037002.47
127 rdf:rest Nd849f140bddc499b863ce1dc6b85eecb
128 N1e0efc7bafa14d11beefeffd23782e04 schema:name Springer Nature - SN SciGraph project
129 rdf:type schema:Organization
130 N1e790e9a61a440c984b543da35d5b252 schema:volumeNumber 4
131 rdf:type schema:PublicationVolume
132 N20c099587eaa4956b23dc4ea06907178 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
133 schema:name Melanoma
134 rdf:type schema:DefinedTerm
135 N261f8efcea90484ba8e8c37643ab8c91 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
136 schema:name Proto-Oncogene Proteins B-raf
137 rdf:type schema:DefinedTerm
138 N28f9db32e07848799b8f141435f88207 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
139 schema:name Signal Transduction
140 rdf:type schema:DefinedTerm
141 N39fca23ab92c4726bbb12272cf863576 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
142 schema:name Mice, Nude
143 rdf:type schema:DefinedTerm
144 N3aa3ebefcf4840168fb97c2a8a55d96c schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
145 schema:name Proto-Oncogene Proteins c-akt
146 rdf:type schema:DefinedTerm
147 N3abf8682c8f143ed9499966c3d26f807 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
148 schema:name Animals
149 rdf:type schema:DefinedTerm
150 N40b50499abb84f5080724459d0e5c473 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
151 schema:name Lentivirus
152 rdf:type schema:DefinedTerm
153 N4d67c3cd48c341fabd64648dba7b736e schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
154 schema:name Indoles
155 rdf:type schema:DefinedTerm
156 N4f7f1ed906e049e79a612b8fef70d8b6 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
157 schema:name CREB-Binding Protein
158 rdf:type schema:DefinedTerm
159 N5259caf10480403f9d70e75c50f01681 schema:name pubmed_id
160 schema:value 24201813
161 rdf:type schema:PropertyValue
162 N59128692901b487cabf53b2501ff9b81 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
163 schema:name Drug Resistance, Neoplasm
164 rdf:type schema:DefinedTerm
165 N5b258162b0a942bfadd94e87c8085d03 schema:issueNumber 11
166 rdf:type schema:PublicationIssue
167 N5e6a238a039848fd817aebe12229908a rdf:first sg:person.01210116316.18
168 rdf:rest N1cab3baa5b7d47c5ab00589eeffc130e
169 N62243a9d010449448a92d4ca7f9a448d schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
170 schema:name Chromatin Immunoprecipitation
171 rdf:type schema:DefinedTerm
172 N64688cf11a91424fb249fbf2720a9fd7 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
173 schema:name RNA, Small Interfering
174 rdf:type schema:DefinedTerm
175 N655c33b9449e4cc9b4434ec28a3c80f3 rdf:first sg:person.01362755716.08
176 rdf:rest N7a251a736709458f9c503116bd07134a
177 N6ce6e9ca0ad74a21825c6b36e8db3042 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
178 schema:name Repressor Proteins
179 rdf:type schema:DefinedTerm
180 N7a251a736709458f9c503116bd07134a rdf:first sg:person.01246527316.15
181 rdf:rest N97705ed451844c6197fe615d6ee336e2
182 N7f7330600132487ca81408e2c66e1c6d schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
183 schema:name Mice
184 rdf:type schema:DefinedTerm
185 N85f851cd0391496591abb638e6799cd7 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
186 schema:name Vemurafenib
187 rdf:type schema:DefinedTerm
188 N8b4e5659d4d2449b93e4c7212aa86ca7 rdf:first sg:person.01276020470.05
189 rdf:rest N9c7df6be5fdd45768198e6ea43276912
190 N97705ed451844c6197fe615d6ee336e2 rdf:first sg:person.0617201523.26
191 rdf:rest Naeee4c22609f444e98de45c83f4bbb3f
192 N9c7df6be5fdd45768198e6ea43276912 rdf:first sg:person.01154115445.79
193 rdf:rest N5e6a238a039848fd817aebe12229908a
194 N9e18f42a2d9542559e6513ada938184a schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
195 schema:name Reverse Transcriptase Polymerase Chain Reaction
196 rdf:type schema:DefinedTerm
197 Naeee4c22609f444e98de45c83f4bbb3f rdf:first sg:person.0664165567.96
198 rdf:rest N8b4e5659d4d2449b93e4c7212aa86ca7
199 Nb289c52af2824486b7391a717a416d23 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
200 schema:name Carboxypeptidases
201 rdf:type schema:DefinedTerm
202 Nb6c3db903be14a0e86e22aedfa6391f6 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
203 schema:name Cell Line, Tumor
204 rdf:type schema:DefinedTerm
205 Nb7ec49ff11cd412da1f71872848d6049 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
206 schema:name NF-kappa B
207 rdf:type schema:DefinedTerm
208 Nd849f140bddc499b863ce1dc6b85eecb rdf:first sg:person.01245131545.13
209 rdf:rest rdf:nil
210 Ndbbd833950644a3586969dd5ae326fb8 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
211 schema:name Humans
212 rdf:type schema:DefinedTerm
213 Ndf503c458a5447a7b148a01d8f260f08 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
214 schema:name In Vitro Techniques
215 rdf:type schema:DefinedTerm
216 Ne4ad37f4e6104716b1504c53c3d3ecc6 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
217 schema:name Sulfonamides
218 rdf:type schema:DefinedTerm
219 Nfa59b192912b434e8d4a5c4c6c42445f schema:name dimensions_id
220 schema:value pub.1031496643
221 rdf:type schema:PropertyValue
222 anzsrc-for:06 schema:inDefinedTermSet anzsrc-for:
223 schema:name Biological Sciences
224 rdf:type schema:DefinedTerm
225 anzsrc-for:0601 schema:inDefinedTermSet anzsrc-for:
226 schema:name Biochemistry and Cell Biology
227 rdf:type schema:DefinedTerm
228 anzsrc-for:11 schema:inDefinedTermSet anzsrc-for:
229 schema:name Medical and Health Sciences
230 rdf:type schema:DefinedTerm
231 anzsrc-for:1112 schema:inDefinedTermSet anzsrc-for:
232 schema:name Oncology and Carcinogenesis
233 rdf:type schema:DefinedTerm
234 sg:grant.6979921 http://pending.schema.org/fundedItem sg:pub.10.1038/cddis.2013.441
235 rdf:type schema:MonetaryGrant
236 sg:journal.1042939 schema:issn 2041-4889
237 schema:name Cell Death & Disease
238 schema:publisher Springer Nature
239 rdf:type schema:Periodical
240 sg:person.01154115445.79 schema:affiliation grid-institutes:grid.12955.3a
241 schema:familyName Wu
242 schema:givenName Q
243 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01154115445.79
244 rdf:type schema:Person
245 sg:person.01210116316.18 schema:affiliation grid-institutes:grid.266842.c
246 schema:familyName Zhang
247 schema:givenName X D
248 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01210116316.18
249 rdf:type schema:Person
250 sg:person.01245131545.13 schema:affiliation grid-institutes:grid.59053.3a
251 schema:familyName Wu
252 schema:givenName M
253 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01245131545.13
254 rdf:type schema:Person
255 sg:person.01246527316.15 schema:affiliation grid-institutes:grid.59053.3a
256 schema:familyName Jin
257 schema:givenName L
258 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01246527316.15
259 rdf:type schema:Person
260 sg:person.01276020470.05 schema:affiliation grid-institutes:grid.1013.3
261 schema:familyName Scolyer
262 schema:givenName R A
263 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01276020470.05
264 rdf:type schema:Person
265 sg:person.01362755716.08 schema:affiliation grid-institutes:grid.186775.a
266 schema:familyName Hu
267 schema:givenName W
268 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01362755716.08
269 rdf:type schema:Person
270 sg:person.0617201523.26 schema:affiliation grid-institutes:grid.266842.c
271 schema:familyName Jiang
272 schema:givenName C C
273 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0617201523.26
274 rdf:type schema:Person
275 sg:person.0664165567.96 schema:affiliation grid-institutes:grid.452919.2
276 schema:familyName Long
277 schema:givenName G V
278 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0664165567.96
279 rdf:type schema:Person
280 sg:person.0670037002.47 schema:affiliation grid-institutes:grid.59053.3a
281 schema:familyName Mei
282 schema:givenName Y
283 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0670037002.47
284 rdf:type schema:Person
285 sg:pub.10.1038/378092a0 schema:sameAs https://app.dimensions.ai/details/publication/pub.1014005971
286 https://doi.org/10.1038/378092a0
287 rdf:type schema:CreativeWork
288 sg:pub.10.1038/43466 schema:sameAs https://app.dimensions.ai/details/publication/pub.1049854869
289 https://doi.org/10.1038/43466
290 rdf:type schema:CreativeWork
291 sg:pub.10.1038/nature00766 schema:sameAs https://app.dimensions.ai/details/publication/pub.1023536940
292 https://doi.org/10.1038/nature00766
293 rdf:type schema:CreativeWork
294 sg:pub.10.1038/nature09626 schema:sameAs https://app.dimensions.ai/details/publication/pub.1035733152
295 https://doi.org/10.1038/nature09626
296 rdf:type schema:CreativeWork
297 sg:pub.10.1038/nature09627 schema:sameAs https://app.dimensions.ai/details/publication/pub.1005907434
298 https://doi.org/10.1038/nature09627
299 rdf:type schema:CreativeWork
300 sg:pub.10.1038/nature10662 schema:sameAs https://app.dimensions.ai/details/publication/pub.1028208693
301 https://doi.org/10.1038/nature10662
302 rdf:type schema:CreativeWork
303 sg:pub.10.1038/nature10868 schema:sameAs https://app.dimensions.ai/details/publication/pub.1038374700
304 https://doi.org/10.1038/nature10868
305 rdf:type schema:CreativeWork
306 sg:pub.10.1038/nature11183 schema:sameAs https://app.dimensions.ai/details/publication/pub.1053677952
307 https://doi.org/10.1038/nature11183
308 rdf:type schema:CreativeWork
309 sg:pub.10.1038/nature11249 schema:sameAs https://app.dimensions.ai/details/publication/pub.1006053948
310 https://doi.org/10.1038/nature11249
311 rdf:type schema:CreativeWork
312 sg:pub.10.1038/ncomms1727 schema:sameAs https://app.dimensions.ai/details/publication/pub.1011476380
313 https://doi.org/10.1038/ncomms1727
314 rdf:type schema:CreativeWork
315 sg:pub.10.1038/onc.2011.424 schema:sameAs https://app.dimensions.ai/details/publication/pub.1052459700
316 https://doi.org/10.1038/onc.2011.424
317 rdf:type schema:CreativeWork
318 grid-institutes:grid.1013.3 schema:alternateName Discipline of Pathology, University of Sydney; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital; Melanoma Institute Australia, Sydney, NSW, Australia
319 schema:name Discipline of Pathology, University of Sydney; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital; Melanoma Institute Australia, Sydney, NSW, Australia
320 rdf:type schema:Organization
321 grid-institutes:grid.12955.3a schema:alternateName State Key Laboratory of Cellular Stress Biology, School of Life sciences, Xiamen University, Xiamen, China
322 schema:name State Key Laboratory of Cellular Stress Biology, School of Life sciences, Xiamen University, Xiamen, China
323 rdf:type schema:Organization
324 grid-institutes:grid.186775.a schema:alternateName Department of Immunology, Anhui Medical University, Anhui, China
325 schema:name Department of Immunology, Anhui Medical University, Anhui, China
326 Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Anhui, China
327 rdf:type schema:Organization
328 grid-institutes:grid.266842.c schema:alternateName School of Biomedical Science and Pharmacy, University of Newcastle, Newcastle, NSW, Australia
329 schema:name School of Biomedical Science and Pharmacy, University of Newcastle, Newcastle, NSW, Australia
330 rdf:type schema:Organization
331 grid-institutes:grid.452919.2 schema:alternateName Melanoma Institute Australia and Westmead Institute for Cancer Research, University of Sydney, Sydney, NSW, Australia
332 schema:name Melanoma Institute Australia and Westmead Institute for Cancer Research, University of Sydney, Sydney, NSW, Australia
333 rdf:type schema:Organization
334 grid-institutes:grid.59053.3a schema:alternateName Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Anhui, China
335 schema:name Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Anhui, China
336 rdf:type schema:Organization
 




Preview window. Press ESC to close (or click here)


...