Examples BCR-ABL kinase Dom ne is inactive again. Examples of mutations that destabilize the inactive conformation to be those residues Glu255, Gly250 and INCB018424 Ruxolitinib Tyr253 in the P loop of Kinasedom ne. Patients and in vitro design an amount of more than 50 different point mutations, have been described in a more or less pronounced Gte resistance to imatinib. Most of these mutations are relatively rare, and the h Most common mutations account for 60 of all 70 mutations. In patient samples and in vitro generated mutants of imatinib resistance is always associated with mutations in the kinase Dom ne, including normal activation loop, P-loop and the hinge region, the C-and N-terminal lobe of the Kinasedom ne connects for YEARS engined form the ATP-binding cleft. The location of the most important changes In the kinase Dom ne is shown in Figure 2.
Zus Tzlich this Kinasedom Ne mutations, mutants generated AP24534 in the laboratory and in patients mutations have been identified in other regions also adorns au Outside the kinase Dom ne. These regions such as SH3, SH2, and the linker between the SH2 and kinase Dom ne necessary to maintain the inactive conformation of the kinase. In vitro studies have shown that various imatinib-resistant mutants k Can have different oncogenic potential, t is a ranking of the Verarbeitungskapazit Tyr253Phe, Glu255Lys wtBcr Abl Thr315Ile His396Pro Met351Thr. Both mutations with gr Erer Verarbeitungskapazit t are also two of the h Most common mutations detected in patients.
In particular, the P-loop mutations in conjunction with the Thr315Ile mutation h More frequently observed in patients with advanced disease and seem to be closely associated with the progression of chronic phase and accelerated phase or blast crisis. Several studies suggest that imatinib-resistant mutations k Can w During treatment with imatinib occur. However, allowed highly sensitive detection of PCR assays and denaturing high performance liquid chromatography detection of mutations in newly diagnosed and treated low, but imatinib na Fs and all CML patients prior to treatment with imatinib. Therefore, imatinib-resistant mutations before treatment with imatinib also exist in a small subclone of tumor cells. Target Bcr Abl independent Ngig independent Dependence resistance appears to be a rare phenomenon Ph In patients with myeloid leukemia His chemistry With newly diagnosed chronic.
Less than 5 patients do not respond to treatment with the standard dose of imatinib 400 mg per day. In contrast, patients with advanced CML h Frequently resistant Bcr Abl prim Re inhibition. Only about 30 patients will respond to the accelerated phase or blast phase CML to this treatment. Recent research has independently on the involvement of Bcr Abl-Dependent way, the progression of the disease, especially PI3K and mTOR kinases of the Src family focused foreign Sen. Lyn and Src survival of the cell and are also in support of the development of certain Leuk Premiums Bcr Abl charge crucial. Bcr Abl positive cells in the presence of continuous imatinib show reduced levels of Bcr Abl and an increase in the expression of Src kinases cultured. R Src kinase of Imatinib resistance was verst of the fi nd Been strengthened, that siRNA-mediated inhibition of Ly