Chonnam Med J.  2014 Dec;50(3):102-111. 10.4068/cmj.2014.50.3.102.

OCT-1, ABCB1, and ABCG2 Expression in Imatinib-Resistant Chronic Myeloid Leukemia Treated with Dasatinib or Nilotinib

• Kim YK
• Lee SS
• Jeong SH
• Ahn JS
• Yang DH
• Lee JJ
• Shin MG
• Kim HJ

• KMID: 2172154
• DOI: http://doi.org/10.4068/cmj.2014.50.3.102

Abstract

This study explored drug transporter expression levels and their impact on clinical response to imatinib and second-generation tyrosine kinase inhibitors (TKIs) in imatinib- resistant chronic myeloid leukemia (CML). Imatinib-resistant chronic phase CML patients treated with dasatinib (n=10) and nilotinib (n=12) were enrolled. The mRNA expression of the OCT-1, ABCG2, and ABCB1 genes was quantified by using paired bone marrow samples obtained before administering imatinib and at the point of detecting imatinib resistance (just before starting second-generation TKIs). The expression levels of OCT-1 and ABCG2 were lower in follow-up than in imatinib-naive samples. ABCB1 revealed highly variable expression levels before and after imatinib treatment. In addition, median ABCB1 expression in follow-up samples was lower in patients achieving complete cytogenetic response or major molecular response during imatinib treatment than in failed patients. Higher ABCG2 expression in imatinib-exposed samples showed a negative impact on optimal response to dasatinib. Patients with higher ABCG2 expression in imatinib-exposed samples also had shorter progression- free survival with dasatinib treatment. However, no significant correlation was found between these drug transporter expression levels in imatinib-naive or imatinib- exposed samples and responses to nilotinib. In imatinib-resistant CML, OCT-1 and ABCG2 mRNA expression decreased after imatinib treatment. Patients with higher ABCG2 expression in imatinib-exposed samples showed poor treatment outcome with dasatinib. On the other hand, a higher expression level of ABCB1 in imatinib-exposed samples did not affect second-generation TKI responses but was correlated with poor imatinib responses.

Keyword

ABCB1 protein; ABCG2 protein; Myeloid leukemia; Imatinib

MeSH Terms

Bone Marrow
Cytogenetics
Follow-Up Studies
Hand
Humans
Leukemia, Myelogenous, Chronic, BCR-ABL Positive*
Leukemia, Myeloid
Protein-Tyrosine Kinases
RNA, Messenger
Treatment Outcome
Dasatinib
Imatinib Mesylate
Protein-Tyrosine Kinases
RNA, Messenger

Figure

• 

  FIG. 1 mRNA expression of OCT-1 (A), ABCG2 (B), and ABCB1 (C) before and after imatinib exposure (n=22). Each column represents the median (range) of three independent experiments performed in duplicate at each time point.

• 

  FIG. 2 ABCB1 mRNA expression levels according to the treatment outcomes of imatinib (n=22). ABCB1 mRNA expression levels before (A) and after (B) imatinib treatment in patients achieving CCyR or no CCyR. ABCB1 mRNA expression levels before (C) and after imatinib treatment (D) in patients achieving MMR or no MMR. CCyR: complete cytogenetic response, MMR: major molecular response, pos: positive, neg: negative.

• 

  FIG. 3 ABCG2 mRNA expression levels in imatinib-exposed samples according to the treatment outcomes of dasatinib (n=10). ABCG2 mRNA expression levels in imatinib-exposed samples in patients achieving CCyR and no CCyR (A), MMR or no MMR (B), and optimal response or failure (C). CCyR: complete cytogenetic response, MMR: major molecular response, pos: positive, neg: negative.

• 

  FIG. 4 Time to achieving optimal responses and PFS according to the ABCG2 mRNA expression after dasatinib treatment. (A) Time to achieving CCyR. (B) Time to achieving MMR. (C) PFS with dasatinib treatment. PFS: progression-free survival, CCyR: complete cytogenetic response, MMR: major molecular response.

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