Overcoming resistance in chronic myelogenous leukemia

• Published in: Leukemia & lymphoma Vol. 50; no. 11; pp. 1785 - 1793
• Main Authors: Cooper, Susannah, Giles, Francis J., Savona, Michael R.
• Format: Journal Article
• Language: English
• Published: United States Informa UK Ltd 01.11.2009; Taylor & Francis
• Subjects: Benzamides - therapeutic use; chemotherapeutic approaches; Drug Resistance, Neoplasm - drug effects; Fusion Proteins, bcr-abl - antagonists & inhibitors; Fusion Proteins, bcr-abl - genetics; Fusion Proteins, bcr-abl - metabolism; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Leukemic progenitor cells; Models, Biological; myeloid leukemias and dysplasias; pharmacotherapeutics; Piperazines - therapeutic use; Protein Kinase Inhibitors - therapeutic use; Pyrazoles - therapeutic use; Pyrimidines - therapeutic use; Signal Transduction - drug effects; signaling therapies; stem and primitive progenitor cells
• ISSN: 1042-8194; 1029-2403
• DOI: 10.3109/10428190903267559

Chronic myeloid leukemia is defined by the acquired genetic mutation, t(9;22), which leads to the fusion-protein BCR-ABL. Prior to the development of imatinib mesylate (Gleevec), treatment was limited and provided only limited survival benefit. Imatinib has dramatically changed the course of the disease and has led to the significantly prolonged survival in the majority of patients. However, there is growing concern for resistance to imatinib and to subsequent second generation tyrosine kinase inhibitors (dasatinib and nilotinib) due to the T315I mutation. With no currently approved effective treatment for TKI-resistant CML with the T315I mutation, molecularly-based, targeted drug development has focused on several strategies to overcome resistance. In this review, we describe agents which overcome the T315I mutation, as well as native BCR-ABL, via several mechanisms, including increased degradation of BCR-ABL, optimization of direct inhibition of the BCR-ABL kinase, inhibition of BCR-ABL-mediated cell growth via interruption of the BCR-ABL-mediated transcription, protein synthesis or post-translational modification, all of which lead to decreased proliferation and malignant cell death.