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

Laura N Eadie,Deborah L White,Timothy P Hughes,Connie J Eaves

doi:10.1371/journal.pone.0161470

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.

Highlights

Chronic myeloid leukemia (CML) is a malignant disorder of the blood stem cells characterized by the presence of the Philadelphia chromosome which gives rise to the BCR-ABL tyrosine kinase[1, 2]
K562 #6 NIL cells were assessed for resistance to imatinib and dasatinib and again demonstrated significantly increased IC50 when compared with control cells (20.5 μM vs. 3.3 μM, p = 0.004 and 11.7 nM vs. 5.6 nM, p
These results were confirmed by cell viability assays (92% vs. 29% in 5 μM imatinib and 74% vs. 21% in 500 nM dasatinib, p

Summary

Introduction

Chronic myeloid leukemia (CML) is a malignant disorder of the blood stem cells characterized by the presence of the Philadelphia chromosome which gives rise to the BCR-ABL tyrosine kinase[1, 2]. Tyrosine kinase inhibitors (TKIs), such as imatinib[3], and the second generation inhibitors nilotinib[4] and dasatinib[5], act by selectively binding to the BCR-ABL kinase domain to inhibit kinase activity and subsequent downstream oncogenic signaling[6]. Resistance to second generation TKIs has been observed[10, 11]. There are several overlapping modes of resistance to TKIs, which can be broadly classified as BCR-ABL dependent and independent.

Methods

Results

Conclusion