title: AEBP1 upregulation confers acquired resistance to BRAF (V600E) inhibition in melanoma.
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.
authors.affiliation: 1] Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Anhui, China [2] Department of Immunology, Anhui Medical University, Anhui, China.
authors.forename: W
authors.initials: W
authors.lastname: Hu
authors.forename: L
authors.initials: L
authors.lastname: Jin
authors.forename: C C
authors.initials: CC
authors.lastname: Jiang
authors.forename: G V
authors.initials: GV
authors.lastname: Long
authors.forename: R A
authors.initials: RA
authors.lastname: Scolyer
authors.forename: Q
authors.initials: Q
authors.lastname: Wu
authors.forename: X D
authors.initials: XD
authors.lastname: Zhang
authors.forename: Y
authors.initials: Y
authors.lastname: Mei
authors.forename: M
authors.initials: M
authors.lastname: Wu
mesh_terms: D000818:Animals; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism; D002268:Carboxypeptidases / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D016086:Lentivirus / Q000235:genetics; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology; D000077484:Vemurafenib
chemical_list: C484818:AEBP1 protein, human; D007211:Indoles; D016328:NF-kappa B; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D013449:Sulfonamides; D000077484:Vemurafenib; D050882:CREB-Binding Protein; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D002268:Carboxypeptidases