Since different kinase inhibitor Crenolanib mechanisms may be involved in intrinsic and acquired melphalan resist ance, more work needs to be done using different cell models to determine the different functions of APE1 in intrinsic and acquired melphalan resistance. Background The v raf murine sarcoma viral oncogene homolog B1 is one of three RAF genes localized on chromosome 7q34. This gene encodes a cytoplasmic serine threonine pro tein kinase of the RAF family. RAF kinases are part of the mitogen activated protein kinase pathway in volved in cell growth, survival and differentiation. Inhibitors,Modulators,Libraries BRAF mutations play an important role in 40 70% of malignant melanomas, 45% of papillary thyroid cancers and 10% of colorectal cancers besides ovarian, breast and lung cancers. According to the COSMIC database 44% of the melanomas harbor BRAF mutations and 97.

1% of these Inhibitors,Modulators,Libraries mutations are localized in codon 600 of the BRAF gene. The most common variation Inhibitors,Modulators,Libraries is a substitution of valine to glutamic acid at codon 600. Less common mutations are substitutions of valine to lysine, to arginine, to leu cin or to aspartic acid, mutations affect ing codon 597, codon 594 and mutations in codon 601 resulting in the exchange of lysine to glutamic acid. The approval of vemurafenib in the US 2011 and in Europe 2012 improved the therapy of not resectable or metastatic melanoma. Vemurafenib exhibits an approxi mately 30 fold selectivity for p. V600E mutated compared to wildtype BRAF melanomas. In addition, patients car rying a p. V600K mutation included in the BRIM 3 study showed response to this inhibitor.

In a phase I trial, a 70% response rate to vemurafenib among 32 genotype selected metastatic melanoma patients was observed. Recent in vitro and in vivo experiments indicate that vemurafenib might have an effect in patients with rare mutations Inhibitors,Modulators,Libraries in codon 600 of the BRAF gene as for instance p. V600D or p. V600R. Furthermore, dab Inhibitors,Modulators,Libraries rafenib, another selective BRAF inhibitor shows good clinical response rates not only for patients with p. V600E or p. V600K mutations but also in patients carrying a p. V600R, p. V600M or a double p. mutation giving new therapy options for melanoma patients with rare BRAF mutations. The FDA approved vemurafenib with the cobas BRAF V600 test as companion diagnostic tool.

The Euro pean Medicine Agencys Committee for Human Medicinal Products approved vemurafenib in February 2012 with two main differences to Deltarasin? the FDA approval, a companion diagnostic test was not defined and treatment option is given for patients with melanomas carrying any mutation in codon 600 of the BRAF gene. Because a mutation in codon 600 determines eligibility for BRAF inhibitor treatment, several molecular screening methods have been developed. However, the level of validation and characterization of the performance features is not defined.