Activity of the Aurora Kinase inhibitor VX-680 against Bcr/Abl positive acute lymphoblastic leukemias

摘要: The emergence of resistance to tyrosine kinase inhibitors due point mutations in Bcr/Abl is a challenging problem for Philadelphia chromosome–positive (Ph-positive) acute lymphoblastic leukemia (ALL) patients, especially those with the T315I mutation, against which neither nilotinib or dasatinib shows significant activity. VX-680 pan-Aurora inhibitor active all proteins but has not been extensively examined preclinical models Ph-positive ALL. Here, we have tested treatment Bcr/Abl-positive ALL when leukemic cells are protected by presence stroma. Under these conditions, showed effects on primary human both and without including ablation phosphorylation downstream Bcr/Abl, decreased viability, induction apoptosis. However, drug 3 days followed removal allowed outgrowth abnormal 21 later, culture mouse stroma lower concentrations VX-680, drug-resistant emerged. Combined lacking mutation caused significantly more cytotoxicity than each alone. We suggest that use together second effective as first-line likely be safer useful second-line monotherapy Mol Cancer Ther; 9(5); 1318–27. ©2010 AACR.