Currently, several JAK2 inhibitors w During development and / or clinical courses Test method for identifying mutations Bafetinib in JAK inhibitor resistant MPNs.27 JAK2 is therefore of great importance it. Therefore, we introduced the Y931C, a homologous mutation of JAK1 F958C in WT or JAK2 V617F protein and is selected Hlt for the autonomous proliferation of these cells. All three mutated JAK2 JAK2 but not WT or embroidered on BAF3 cells were able to proliferate in the absence of IL-3. The F Ability to replicate autonomously was with the activation of JAK2 and STAT5 in these cells constitutively associated. Autonomous cell proliferation was measured in the presence of charge of increasing concentrations of the CMP6 INCB018424 or IC50. JAK2 Y931C reduced the sensitivity of the cells as compared to BaF3 INCB018424 JAK2 V617F positive BaF3 cells.
Zus Tzlich showed cells expressing the double mutant JAK2 V617F/Y931C identical sensitivity to inhibitors than 50-fold express Y931C mutant alone, with an increase of 20 to the IC50 compared to cells V658F Tivozanib mutation positive. Similar results were observed when ATP wettbewerbsf other inhibitors HIGEN tested. The resistance of the cells became positive for JAK2 Y931C inhibitor associated with the phosphorylation of JAK2 persistent Pr Presence JAK inhibitor. These results show that the acquisition of a JAK inhibitor resistant mutations such as Y931C cells to JAK2 V617F for growing an m Glicher mechanism of secondary Ren resistance to JAK inhibitor therapy in patients with MPN activated dependent Depends. The discussion is about acceptance of self-sufficiency in growth signals one of the hallmarks of cancer.
28 In this paper, we show that a wide spectrum of spontaneous mutations in one allele of the endogenous JAK1 main mechanism gives, BaF3 F ability, The cytokine independent-dependent cell growth in vitro and in vivo Tumorigenit t secondary vervollst to r ndigen upregulation of transcription JAK1. We use this in vitro model of spontaneous generation you mori a library of cell lines with 25 different mutations of JAK1 novo activation, of which generate 6 targeting two residues Phe958 and Pro960 in the hinge region is located on the periphery of the ATP-binding pocket . The most important feature of these mutations targeting Phe958 and Pro960 is not only that they confinement constitutively active kinase, but also a gr Ere Best RESISTANCE against ATP competitive inhibitors Lich INCB018424, currently used in clinical trials for JAK2 MPNs.
12 The gr te disadvantage V617Fpositive tyrosine kinase inhibitor treatment is the development of a secondary Ren resistance through the acquisition of new mutations caused, as the best example of imatinib resistance mutations in BCR-ABL positive CML.13 several ABL kinase Dom ne BCR mutations confer imatinib resistance have been described, including normal T315I mutation, which the holder seeks Thr315 door ABL kinase. This residue is not Thr gatekeeper in the family of JAK kinases conserved but Phe958 residue, the residue of JAK1 kinase homologous to Phe317 in ABL, which is close to the gatekeeper residue and beyond patients due to positive in mutant imatinib-resistant BCR ABL. 13, 29.30. In the same direction as the non-small cell lung cancer, acquired resistance to gefitinib / erlotinib kinase inhibitors also having a secondary Ren mutation Thr gatekeeper assigned 790 residues of the receptor of the epidermal growth factor.