ABCB1 Overexpression Is a Key Initiator of Resistance to Tyrosine Kinase Inhibitors in CML Cell Lines

• Published in: PloS one Vol. 11; no. 8; p. e0161470
• Main Authors: Eadie, Laura N., Hughes, Timothy P., White, Deborah L.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 18.08.2016; Public Library of Science (PLoS)
• Subjects: Analysis; Antineoplastic Agents - therapeutic use; ATP Binding Cassette Transporter, Subfamily B - metabolism; ATP Binding Cassette Transporter, Subfamily B - physiology; Biology and Life Sciences; Biotechnology; Blotting, Western; Care and treatment; Cell Line, Tumor; Cell lines; Cell Survival; Chronic myeloid leukemia; Dasatinib; Dasatinib - therapeutic use; Dosage and administration; Drug Resistance, Neoplasm - physiology; Drug therapy; Enzyme inhibitors; Flow Cytometry; Humans; Imatinib; Imatinib mesylate; Imatinib Mesylate - therapeutic use; Inhibitory Concentration 50; Kinases; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - enzymology; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism; Medical research; Mutation; Nilotinib; Patients; Protein-tyrosine kinase; Protein-Tyrosine Kinases - antagonists & inhibitors; Pyrimidines - therapeutic use; Real-Time Polymerase Chain Reaction; Research and Analysis Methods; Studies; Tyrosine; Tyrosine kinase inhibitors; Tyrosine metabolism; Australia; South Australia Australia
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0161470

The tyrosine kinase inhibitor (TKI) imatinib has resulted in excellent responses in the majority of Chronic Myeloid Leukaemia (CML) patients; however, resistance is observed in 20-30% of patients. More recently, resistance to the second generation TKIs, nilotinib and dasatinib, has also been observed albeit at a lower incidence. ABCB1 has previously been implicated in TKI export and its overexpression linked to TKI resistance. In this study the dynamics of nilotinib resistance was studied in CML cell lines with particular focus on ABCB1 expression levels during development of resistance. Results revealed ABCB1 overexpression is likely an important initiator of nilotinib resistance in vitro. ABCB1 overexpression was also observed in cell lines as an intermediate step during development of resistance to imatinib and dasatinib in vitro. We conclude that ABCB1 overexpression may provide an initial platform to facilitate development of additional mechanisms for resistance to TKIs. This provides a rationale for investigating this phenomenon in patients undergoing TKI therapy.