title: ABCB1 Overexpression Is a Key Initiator of Resistance to Tyrosine Kinase Inhibitors in CML Cell Lines.
abstract: 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.
authors.affiliation: Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia.|Department of Medicine, University of Adelaide, Adelaide, South Australia.
authors.forename: Laura N
authors.identifier: http://orcid.org/0000-0003-1912-7602
authors.initials: LN
authors.lastname: Eadie
authors.affiliation: Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia.|Department of Medicine, University of Adelaide, Adelaide, South Australia.|Division of Haematology, SA Pathology, Adelaide, South Australia.|Centre for Cancer Biology, Adelaide, South Australia.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Hughes
authors.affiliation: Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia.|Department of Medicine, University of Adelaide, Adelaide, South Australia.|Department of Paediatrics, University of Adelaide, Adelaide, South Australia.
authors.forename: Deborah L
authors.initials: DL
authors.lastname: White
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism / Q000502:physiology; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival; D000069439:Dasatinib / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D005434:Flow Cytometry; D006801:Humans; D000068877:Imatinib Mesylate / Q000627:therapeutic use; D020128:Inhibitory Concentration 50; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000627:therapeutic use; D060888:Real-Time Polymerase Chain Reaction
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; C498826:nilotinib; D000069439:Dasatinib