title: Metastatic melanoma cells with BRAF G469A mutation: nab-paclitaxel better than vemurafenib?
abstract: OBJECTIVE
  BRAF G469A is a missense mutation within exon 11 of the BRAF gene resulting in a constitutively activated enzyme frequently associated with MAP kinase cascade signaling activation. No evidence currently exists about its role in determining sensitivity/resistance to BRAF inhibitors, utilized in the treatment of patients carrying BRAF V600 mutations, and to chemotherapy. The newly established metastatic melanoma (MM) cell line MO-1 was characterized for its sensitivity to vemurafenib and nab-paclitaxel, both already utilized for the treatment of MM.
  
  
  METHODS
  All analyses were carried out by comparing results with those found in MM cells wild type for BRAF or mutated in V600. In addition, cellular effectors were investigated by ELISA kits, western blotting and flow cytometry.
  
  
  RESULTS
  The exposure to vemurafenib inhibited MO-1 cell proliferation at concentrations similar to those obtained in vemurafenib-resistant melanoma models, and an explanation of this sensitivity is the strong activation of Erk1/2 and the low expression of MITF. Nab-paclitaxel strongly reduced proliferation of MO-1 cells perhaps for the very low expression level of PMEL17, transcriptionally regulated by MITF and negatively involved in determining sensitivity to taxanes.
  
  
  CONCLUSIONS
  Thus, the mutation BRAF G469A in MM might be related to a weak effectiveness of therapy with BRAF inhibitors and a promising therapeutic approach may be with nab-paclitaxel.
authors.affiliation: Clinical and Preclinical Pharmacology Lab, National Cancer Research Centre Istituto Tumori Giovanni Paolo II, Viale O. Flacco, 65, 70124, Bari, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Porcelli
authors.forename: Gabriella
authors.initials: G
authors.lastname: Guida
authors.forename: Stefania
authors.initials: S
authors.lastname: Tommasi
authors.forename: Michele
authors.initials: M
authors.lastname: Guida
authors.forename: Amalia
authors.initials: A
authors.lastname: Azzariti
mesh_terms: D000418:Albumins / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D008545:Melanoma / Q000188:drug therapy* / Q000556:secondary; D020125:Mutation, Missense; D017239:Paclitaxel / Q000494:pharmacology* / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D000077484:Vemurafenib
chemical_list: C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D000970:Antineoplastic Agents; D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D017239:Paclitaxel