The list of the BRAF inhibitor currently in the pr Clinical and clinical evaluation Including XL281, SB590885, GDC 0879, GSK2118438, AZ628 and PLX4032. Among them, the PLX4032 and its analogue, PLX4720, has been studied very extensively. Treatment of melanoma cell lines and xenografts of M nozzles With PLX4032/4720 led to both XL147 the G1 phase of the cell cycle arrest and induction of apoptosis. The effects of PLX4032 found certain BRAF mutation have been, and equivalent responses were observed in models of melanoma with both heterozygous and homozygous BRAF mutations. No anti-proliferative or cytotoxic effects were observed in cultured melanoma cells that had no mutation in the BRAF gene. Interestingly, all BRAF mutated melanoma cell lines also sensitive to PLX4032 PLX4720 and so, with some cell lines with intrinsic resistance.
In Phase I clinical trials Axitinib vemurafenib resulted in a significant Ma of tumor shrinkage in 80% of patients with melanoma harbored BRAF V600E mutation. This is an unprecedented result of a clinical trial of melanoma and fast at it Opening of Phase II and two Phase III as monotherapy. The Phase III study concluded vemurafenib more tt, when the prim Re endpoint of progression-free survival was achieved and the data were submitted to the FDA for the beh Rdliche approval. Although the test results were very impressive vemurafenib, responses were unfortunately short with most patients ultimately not therapy and become resistant. To manage and develop strategies to overcome acquired resistance to BRAF inhibitor is now the big challenge for e melanoma research. These data show that the resistance to vemurafenib complex and multifactorial.
Studies have already shown that the resistance obtained by the receptor tyrosine kinase pathway Ht acquisition of activating mutations in NRAS, new mutations in MEK1 and up regulation of MAP3K8 may be mediated. Although the mechanisms of resistance are currently reported to be the most diverse, with the application of new MAPK and / or a Erh Increase the PI3K/Akt/mTOR signaling associated. Clinical trials are underway to the combination of inhibitors of MEK and BRAF V600E BRAF mutated melanoma with the combination trials with BRAF inhibitor AKT validate the start in the near future. The ultimate goal of these studies is to define an optimal combination therapy strategy for the time to recurrence and improved overall survival laughed Ngern.
Using proteomics to the mechanisms of resistance to BRAF inhibitor intrinsic Approximately 20% of patients with V600E BRAF mutated melanoma Phase I trial seems to be intrinsically resistant to vemurafenib and met not understand RECIST criteria for response. Although only MAPK addicted melanomas are known to require signaling activity T in many other M Opportunities. With the PI3K/Akt pathway thought to be particularly important for the development and progression of malignant melanoma times In a recent study, our laboratory has the loss of expression of tumor suppressor phosphatase and tensin homolog the how predictive adversely Chtigter apoptotic response in BRAF inhibition was identified.