New targeted therapies for chronic myelogenous leukemia: opportunities to overcome imatinib resistance.
The advent of tyrosine kinase inhibitors (TKIs) has ushered in a new era in the management of chronic myelogenous leukemia (CML). Imatinib, the first TKI to be approved for the treatment of CML and the current standard first-line therapy, has significantly improved the prognosis of patients with CML. Nevertheless, a minority of patients in chronic-phase CML and even more patients with advanced-phase disease demonstrate resistance to imatinib or develop resistance during treatment. In 40% to 50% of cases, this is attributed to the development of mutations that impair the ability of imatinib to bind to and inhibit the constitutively active Bcr-Abl kinase. Consequently, researchers have developed novel, more potent TKIs that can overcome not only Bcr-Abl-dependent mechanisms of resistance, but also those that are Bcr-Abl-independent. These include: dasatinib, a potent dual Bcr-Abl and Src inhibitor; nilotinib, a selective, potent Bcr-Abl inhibitor; bosutinib (SKI-606) and INNO-406 (NS-187), which are both Src-Abl inhibitors; and others. Combination therapy is also being explored concurrently using agents that affect a variety of oncogenic pathways and immune modulation. Herein, we review some of these strategies, particularly those for which clinical data are currently available.
Jabbour
Elias
E
Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Cortes
Jorge
J
O'Brien
Susan
S
Giles
Francis
F
Kantarjian
Hagop
H
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors; D000814:Aniline Compounds / Q000494:pharmacology; D001549:Benzamides; D019496:Cancer Vaccines; D002986:Clinical Trials as Topic; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology; D016044:Fusion Proteins, bcr-abl / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000503:physiopathology; D009570:Nitriles / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
D048868:Adaptor Proteins, Signal Transducing; D000814:Aniline Compounds; D001549:Benzamides; D019496:Cancer Vaccines; D009570:Nitriles; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011804:Quinolines; C499446:TOM1L1 protein, human; D013844:Thiazoles; C471992:bosutinib; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib; C506918:bafetinib; D000069439:Dasatinib