Impact of BCR-ABL mutations on patients with chronic myeloid leukemia

• Published in: Cell cycle (Georgetown, Tex.) Vol. 10; no. 2; pp. 250 - 260
• Main Authors: Hochhaus, Andreas, Rosée, Paul La, Müller, Martin C., Ernst, Thomas, Cross, Nicholas C.P.
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 15.01.2011
• Subjects: Antineoplastic Agents - therapeutic use; Benzamides; Binding; Biology; Bioscience; Calcium; Cancer; Cell; Cycle; Dasatinib; Disease-Free Survival; Drug Resistance, Neoplasm - genetics; Fusion Proteins, bcr-abl - antagonists & inhibitors; Fusion Proteins, bcr-abl - genetics; Fusion Proteins, bcr-abl - metabolism; Humans; Imatinib Mesylate; Landes; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism; Mutation; Organogenesis; Piperazines - therapeutic use; Proteins; Pyrimidines - therapeutic use; Thiazoles - therapeutic use
• ISSN: 1538-4101; 1551-4005
• DOI: 10.4161/cc.10.2.14537

Therapies that target BCR-ABL in chronic myeloid leukemia, including imatinib, dasatinib and nilotinib, have dramatically improved patient outcome. BCR-ABL mutations, however, contribute to treatment resistance by disrupting drug contact sites or causing conformational changes thus making contact sites inaccessible. Clinical data indicate that developing BCR-ABL mutations during imatinib treatment is predictive for shorter progression-free survival, and that outcomes may depend on mutation type or location. In vitro, dasatinib and nilotinib inhibit most imatinib-resistant BCR-ABL mutations, except for T315I. In clinical studies, other mutations associated with treatment resistance include V299L, T315A, and F317I/L for dasatinib and Y253F/H, E255K/V, and F359C/V for nilotinib. Evaluating patients with clinical signs of resistance for BCR-ABL mutations is an important component of disease monitoring, potentially facilitating selection of subsequent therapy. First-line treatment with dasatinib or nilotinib instead of imatinib may reduce emergence of resistance but novel agents are needed to overcome the problematic T315I mutation.