Targeted CML therapy: controlling drug resistance, seeking cure.
Targeted cancer therapy with imatinib (Gleevec) has the capability to drive chronic myeloid leukemia (CML) into clinical remission. Some patients, particularly those with advanced disease, develop resistance to imatinib. To counteract this problem, two new BCR-ABL kinase inhibitors for imatinib-refractory disease are currently in clinical trials: the imatinib derivative AMN107 and the dual-specificity SRC/ABL inhibitor dasatinib. Using imatinib to reduce leukemic burden also facilitates the detailed investigation into how the persistence of CML disease depends on BCR-ABL signaling, particularly within the leukemic stem cell compartment. Mathematical models of drug resistance and disease relapse, in addition to experimental systems that recapitulate crucial aspects of advanced disease have deepened our understanding of CML biology. Together, these advances are contributing to a high level of disease control, and might ultimately lead to disease eradication.
O'Hare
Thomas
T
Howard Hughes Medical Institute, Oregon Health & Science University Cancer Institute, L592, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
Corbin
Amie S
AS
Druker
Brian J
BJ
D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D008954:Models, Biological; D014411:Neoplastic Stem Cells / Q000187:drug effects; D010879:Piperazines / Q000627:therapeutic use; D017354:Point Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D011743:Pyrimidines / Q000627:therapeutic use; D013844:Thiazoles / Q000627:therapeutic use
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib; D000069439:Dasatinib