Abstract |
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.
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Authors | Elias Jabbour, Jorge Cortes, Susan O'Brien, Francis Giles, Hagop Kantarjian |
Journal | Seminars in hematology
(Semin Hematol)
Vol. 44
Issue 1 Suppl 1
Pg. S25-31
(Jan 2007)
ISSN: 0037-1963 [Print] United States |
PMID | 17292738
(Publication Type: Journal Article, Review)
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Chemical References |
- Adaptor Proteins, Signal Transducing
- Aniline Compounds
- Benzamides
- Cancer Vaccines
- Nitriles
- Piperazines
- Protein Kinase Inhibitors
- Pyrimidines
- Quinolines
- TOM1L1 protein, human
- Thiazoles
- bosutinib
- Imatinib Mesylate
- Protein-Tyrosine Kinases
- Fusion Proteins, bcr-abl
- nilotinib
- bafetinib
- Dasatinib
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Topics |
- Adaptor Proteins, Signal Transducing
(antagonists & inhibitors)
- Aniline Compounds
(pharmacology)
- Benzamides
- Cancer Vaccines
- Clinical Trials as Topic
- Dasatinib
- Drug Resistance, Neoplasm
(drug effects, physiology)
- Fusion Proteins, bcr-abl
(drug effects, genetics)
- Humans
- Imatinib Mesylate
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive
(drug therapy, physiopathology)
- Nitriles
(pharmacology)
- Piperazines
(pharmacology)
- Protein Kinase Inhibitors
(pharmacology)
- Protein-Tyrosine Kinases
(antagonists & inhibitors)
- Pyrimidines
(pharmacology)
- Quinolines
(pharmacology)
- Thiazoles
(pharmacology)
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