Review
Nature Reviews Cancer 7, 345-356 (May 2007) | doi:10.1038/nrc2126
Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukaemia
Ellen Weisberg1, Paul W. Manley2, Sandra W. Cowan-Jacob3, Andreas Hochhaus4 & James D. Griffin5 About the authors
Abstract
Imatinib, a small-molecule ABL kinase inhibitor, is a highly effective therapy for early-phase chronic myeloid leukaemia (CML), which has constitutively active ABL kinase activity owing to the expression of the BCR-ABL fusion protein. However, there is a high relapse rate among advanced- and blast-crisis-phase patients owing to the development of mutations in the ABL kinase domain that cause drug resistance. Several second-generation ABL kinase inhibitors have been or are being developed for the treatment of imatinib-resistant CML. Here, we describe the mechanism of action of imatinib in CML, the structural basis of imatinib resistance, and the potential of second-generation BCR-ABL inhibitors to circumvent resistance.
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Author affiliations
- Dana Farber Cancer Institute, Mayer 540, 44 Binney St, Boston, Massachusetts 02115, USA.
- Novartis Institutes for BioMedical Research, WKL-136.4.86, Basel, CH-4002, Switzerland.
- Novartis Institutes for BioMedical Research, WSJ-088.9.08A, Basel, CH-4056, Switzerland.
- Medizinische Fakultat Mannheim der Universitat Heidelberg III. Medizinische Klinik, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.
- Dana-Farber Cancer Institute, Department of Medical Oncology, 44 Binney Street, Boston, Massachusetts 02115, USA.
Correspondence to: James D. Griffin5 Email: james_griffin@dfci.harvard.edu
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