Melanoma is a deadly malignancy arising from melanocytes, which is responsible for 75% of death cases due to skin cancer. Metastatic melanoma (MM) responds poorly to most anticancer medicines and overall mean survival for patients with MM is 8.5 months.
BRAF is a part of the Ras/Raf/MEK/MAP signal transduction pathway. Approximately 40 to 60% of cutaneous melanomas carry mutations in BRAF that lead to constitutive activation of downstream signaling through the MAPK pathway. 90% are BRAF V600E mutation.
Vemurafenib, recently approved by FDA, is a BRAF inhibitor that has demonstrated activity in patients harboring the V600E BRAF mutation. However, chronic treatment with BRAF inhibitors is associated with development of drug resistance.
Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a membranal glycoprotein, which mediates homophilic interactions, transduces intracellular. CEACAM1 expression on primary melanoma strongly predicts an aggressive disease.
We have previously shown that CEACAM1 protects human melanoma cells by inhibiting human NK and T cell functions in vitro. In addition, CEACAM1 directly confers aggressive features to melanoma cells. MRG1, a murine IgG1 monoclonal antibody, was developed in our lab against human CEACAM1. Evidence shows that blocking CEACAM1 function with MRG1 renders melanoma cells more vulnerable to reactive lymphocytes, in vitro and in vivo.
A number of melanoma cell lines bearing BRAF V600E mutation were tested for CEACAM1 expression and good correlation was demonstrated between the CEACAM1 expression and BRAF V600E mutation.
Our preliminary results show that inhibition of V600E BRAF mutation using Vemurafenib, leads to down regulation of CEACAM1 in melanoma cells.
Our main objective is to understand the interplay between CEACAM1 expression and BRAF mutation in order to improve the therapeutic effect of BRAF mutation inhibitors and to overtake the resistance of melanoma cells to BRAF inhibitors.
