Is the T1799A transversion in Kaposi’s v raf murine viral oncogene homolog B1 gene, a substitution BTZ043 BTZ038 of glutamine leads Acid for valine at position 600 encodes the kinase that is found in about 50% of the tumors. BRAF is a serine / threonine protein kinase, which through specific G protein-BS, the downstream Extracellular rts of growth factor receptors, cytokines, hormones, and the BS / MEK / kinase cascade is Re signal signal activates regulated activation. Change V600E activates RAF kinase constitutively activate the mitogen-activated protein kinase pathway through ERK hyperactivation, the survival of the cells, proliferation, invasion and angiogenesis f Promoted. BRAF mutation acts as a pilot, a state of dependence Oncogene dependence to determine not to respond to an inhibition of MAPK / ERK kinase comments, but show an increased Hte sensitivity to the direct inhibition of BRAF and MEK.
MAPK cascade activation determines the other canals le, to be at different levels. The network also reports of phosphoinositide 3-kinase / AKT murine thymoma viral oncogene homolog inhibited v / mammalian target of rapamycin, is constitutively activated NVP-ADW742 IGF-1R inhibitor in melanoma and may provide compensatory rdern ways to f cell proliferation and survival. Given the relevance of the RAS / BRAF / MAPK were activated in melanoma several inhibitors, by targeting the RAF kinases and shows a certain selectivity of t for the mutated BRAF or MEK kinase targeting produces the downstream. Several of these inhibitors are currently being evaluated in clinical trials.
PLX4032 is a competitive inhibitor of ATP-azaindole derivative specific for BRAF V600E mutant showed promising efficacy in pr Clinical trials. Phase 1-2 clinical trials have shown response rates of over 50% in patients with melanoma BRAFV600E tr Gt mutation, a finding best Ined in a phase 3 trial reported improved overall survival and progression-free. Despite these encouraging signs, a secondary clinical outcome Rer resistance as a common feature and kinase targeted drugs a big problem for the study. Studies of the mechanisms associated with the acquisition of resistance reported different genetic and epigenetic Ver Changes, the activation of ERK by MEK-dependent Independent mechanisms to deal BRAF inhibition, detectable in tumor biopsies from patients who developed resistance to PLX4032 treatment on the clinical response.
These Ver Changes included de novo somatic mutations in MEK1, neuroblastoma RAS viral oncogene homolog or phosphatase and tensin homologous genes, but not in the target gene BRAF and hyperactivation Blutpl Ttchen receptor-derived growth factor, analogue insulin growth factor-1 receptor and MAP3K8 kinases. In this report we have on primary melanoma show Re resistance were obtained by screening a group of patients from genetically characterize BRAFV600E mutated melanoma cell lines that are associated with identification Changes of the Ren cellular Been identified in response to PLX4032. We have the genetic and molecular two melanoma cell lines that exhibited a low sensitivity to PLX4032 as a model of prim R resistance. For genetic characterization, and use an application phosphoproteomic