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


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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.
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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
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101 study
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104 therapy
105 treatment
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