Mechanisms of Resistance to ABL Kinase Inhibition in Chronic Myeloid Leukemia and the Development of Next Generation ABL Kinase Inhibitors

• Published in: Hematology/oncology clinics of North America Vol. 31; no. 4; p. 589
• Main Authors: Patel, Ami B, O'Hare, Thomas, Deininger, Michael W
• Format: Journal Article
• Language: English
• Published: United States 01.08.2017
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological Availability; Biomarkers; Cell Survival - drug effects; Cell Survival - genetics; Dose-Response Relationship, Drug; Drug Discovery; Drug Resistance, Neoplasm - genetics; Fusion Proteins, bcr-abl - antagonists & inhibitors; Fusion Proteins, bcr-abl - chemistry; Fusion Proteins, bcr-abl - genetics; Gene Expression Regulation, Leukemic - drug effects; Humans; Immunotherapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Models, Molecular; Molecular Targeted Therapy; Mutation; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Signal Transduction - drug effects; Structure-Activity Relationship; Chronic myeloid leukemia (CML); Tyrosine kinase inhibitor (TKI); Mutation; Drug resistance; Treatment-free remission (TFR); BCR-ABL1
• ISSN: 1558-1977
• DOI: 10.1016/j.hoc.2017.04.007

Chronic myeloid leukemia is increasingly viewed as a chronic illness; most patients have a life expectancy close to that of the general population. Despite progress made using BCR-ABL1 tyrosine kinase inhibitors (TKIs), drug resistance via BCR-ABL1-dependent and BCR-ABL1-independent mechanisms continues to be an issue. BCR-ABL1-dependent resistance is primarily mediated through oncoprotein kinase domain mutations and usually results in overt resistance to TKIs. However, BCR-ABL1-independent resistance in the setting of effective BCR-ABL1 inhibition is recognized as a major contributor to minimal residual disease. Efforts to eradicate persistent leukemic stem cells have focused on combination therapy.