MK-0457, a novel kinase inhibitor, is active in patients with chronic myeloid leukemia or acute lymphocytic leukemia with the T315I BCR-ABL mutation.
MK-0457 (VX-680) is a small-molecule aurora kinase (AK) inhibitor with preclinical antileukemia activity. The T315I BCR-ABL mutation mediates resistance to imatinib, nilotinib, and dasatinib. MK-0457 has in vitro activity against cells expressing wild-type or mutated BCR-ABL, including the T315I BCR-ABL mutation. Three patients with T315I abl-mutated chronic myeloid leukemia (CML) or Philadelphia chromosome (Ph)-positive acute lymphocytic leukemia (ALL) have achieved clinical responses to doses of MK-04547 that are not associated with adverse events. Higher MK-0457 dose levels were associated with clinical responses and down-regulation of CrkL phosphorylation in leukemia cells. The possible role of AK inhibition in these clinical responses requires further investigation. The currently reported cases are the first observed clinical activity of a kinase inhibitor against the T315I phenotype. The observation of responses in 3 patients with T315I phenotype-refractory CML or Ph-positive ALL, at doses of MK-0457 associated with no significant extramedullary toxicity, is very encouraging.
Giles
Francis J
FJ
Department of Leukemia, M. D. Anderson Cancer Center, 1400 Holcombe Blvd, Box 428, Houston, TX 77030, USA. frankgiles@aol.com
Cortes
Jorge
J
Jones
Dan
D
Bergstrom
Donald
D
Kantarjian
Hagop
H
Freedman
Steven J
SJ
D048868:Adaptor Proteins, Signal Transducing / Q000187:drug effects / Q000378:metabolism; D000328:Adult; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D007262:Infusions, Intravenous; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000187:drug effects / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
D048868:Adaptor Proteins, Signal Transducing; D016044:Fusion Proteins, bcr-abl; D009687:Nuclear Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; C082869:CRKL protein; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines