New insights into the pathophysiology of chronic myeloid leukemia and imatinib resistance.
Chronic myeloid leukemia (CML) was the first human malignant disease to be linked to a single, acquired genetic abnormality. Identification of the BCR-ABL kinase fusion protein and its central role in the pathogenesis of CML provided new opportunities to develop rational molecular targeted therapies. This review provides an update on the underlying pathophysiologies of disease progression and imatinib mesylate resistance, leading to the development of new targeted tyrosine kinase inhibitors for managing CML. Imatinib, a selective inhibitor of BCR-ABL, represents a major success in the era of target-directed cancer chemotherapy. However, patients with advanced CML have been less sensitive to therapy and responses have been short. In addition, treatment resistance is an emerging problem at all disease stages. Insight into factors involved in imatinib resistance and disease progression has highlighted a role for such BCR-ABL-dependent factors as amplification and overexpression of the BCR-ABL gene and the emergence of mutant isoforms of BCR-ABL. However, BCR-ABL-independent factors, including leukemogenic pathways involving kinases other than BCR-ABL, also play a part. In light of the limitations of imatinib against these factors, newer tyrosine kinase inhibitors, including dasatinib (a multitargeted kinase inhibitor of BCR-ABL and Src family kinases) and nilotinib (AMN107, a selective BCR-ABL inhibitor), may provide promising treatment options for patients with CML.
Kantarjian
Hagop M
HM
Department of Leukemia, MD Anderson Cancer Center, Houston, Texas 77030, USA. hkantarj@mdanderson.org
Talpaz
Moshe
M
Giles
Francis
F
O'Brien
Susan
S
Cortes
Jorge
J
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000502:physiology; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology*; D010879:Piperazines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D019061:src-Family Kinases