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.