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.

Pharmacological targeting of guanosine monophosphate synthase suppresses melanoma cell invasion and tumorigenicity

“…41,42 In addition, melanomas are exceptionally resistant to chemotherapy treatment and have a high incidence of relapse. [43][44][45][46][47] Our previous 8 and current studies have revealed a prominent role of deregulated guanylate pools in melanoma progression. Altered expression of enzymes involved in guanylates biosynthesis priming the cells toward an increase in guanylates production occurs already in primary melanomas (GMPR) and peaks at the metastatic stage (IMPDH2, GMPR, and GMPS) (Wawrzyniak et al 8 and Figure 3 and Supplementary Figure S2).…”

RIP1 Kinase Is an Oncogenic Driver in Melanoma

“…The mechanisms regulating cell type-dependent involvement of NF-kB remain to be clarified. Regardless, our results indicate that RIP1 is responsible, at least in part, for constitutive NF-kB activation that is commonly found at high levels in melanoma cells (29,40).…”

“…NF-kB activity assays were performed using an assay kit (Qiagen) as per the manufacturer's instructions (29). Briefly, cells transfected with the NF-kB activity reporter with or without cotransfection with indicated siRNAs or cDNAs were subjected to Dual-Luciferase Reporter Assay (Promega) after desired treatment.…”

Many are better than one - Next Generation Multi-Variate Biomarkers for Precision Oncology

“…While response rates in this sub-population are impressive, approximately half do not respond, and the majority of the responders will eventually acquire resistance [10] . Many genetic mechanisms of resistance have been cataloged [11] , including NF1 loss-of-function mutations [12] , NRAS activating mutations, BRAFV600E splicing variant, MEK1 mutation, COT expression, BRAFV600E amplification, BRAF G469L mutation [13] , concurrent MEK2 mutation and BRAF amplification [14] , AEBP1 upregulation [15] , MAP2K2 and MITF genomic alterations [16] and MEK2 Q60P mutation [17] , all of which result in reactivation of MAPK signaling, as well as the activation of parallel survival pathways such IGF1R/PI3K-AKT signaling [18] .…”