The clinical significance of ABCB1 overexpression in predicting outcome of CML patients undergoing first-line imatinib treatment

Abstract

Tyrosine kinase inhibitor (TKI) therapy results in excellent responses in the majority of patients with chronic myeloid leukaemia. First-line imatinib treatment, with selective switching to nilotinib when patients fail to meet specific molecular targets or for imatinib intolerance, results in excellent overall molecular responses and survival. However, this strategy is less effective in cases of primary imatinib resistance; moreover, 25% of patients develop secondary resistance such that 20-35% of patients initially treated with imatinib will eventually experience treatment failure. Early identification of these patients is of high clinical relevance. Since the drug efflux transporter ABCB1 has previously been implicated in TKI resistance, we determined if early increases in ABCB1 mRNA expression (fold change from diagnosis to day 22 of imatinib therapy) predict for patient response. Indeed, patients exhibiting a high fold rise (⩾2.2, n=79) were significantly less likely to achieve early molecular response (BCR-ABL1 ⩽10% at 3 months; P=0.001), major molecular response (P<0.0001) and MR4.5 (P<0.0001). Additionally, patients demonstrated increased levels of ABCB1 mRNA before the development of mutations and/or progression to blast crisis. Patients with high fold rise in ABCB1 mRNA were also less likely to achieve major molecular response when switched to nilotinib therapy (49% vs 82% of patients with low fold rise). We conclude that early evaluation of the fold change in ABCB1 mRNA expression may identify patients likely to be resistant to first- and second-generation TKIs and who may be candidates for alternative therapy.

LncRNA FENDRR attenuates adriamycin resistance via suppressing MDR1 expression through sponging HuR and miR‐184 in chronic myelogenous leukaemia cells

“…Tyrosine kinase inhibitors (TKIs) and chemotherapy have proven to be highly effective in CML treatment [2]. However, drug transporters, particularly ABCB1 (also known as MDR1, P-glycoprotein, P-gp), play a critical role in drug export and predicate the potential therapeutic responses of CML patients [3][4][5]. Hence, numerous strategies to overcome MDR1-mediated resistance have been explored [6,7].…”

Multi-omic profiling of tyrosine kinase inhibitor-resistant K562 cells suggests metabolic reprogramming to promote cell survival

“…S2, S5), indicating that our models were comparable to others developed in the literature. (28)(29)(30)(31)(32) Ingenuity Pathway Analysis (IPA) performed on the differential expression data for the 370 common genes ( Figure 2C) identified oxidative stress-related and inflammatory processes as altered, e.g. NFkB signaling, as well as decreased signaling by PTEN (a tumor suppressor pathway) and PPAR (a metabolic signaling pathway).…”

Pharmacogenetics and Pharmacogenomics of Targeted Therapeutics in Chronic Myeloid Leukemia

“…Clinical studies have established that ABCB1 expression levels are elevated in advanced stages of CML [42], and that high ABCB1 expression is associated with lower rates of MMR and imatinib resistance [43, 44]. At the molecular level, in vitro studies with the K562 cell line demonstrated that an increase in ABCB1-mediated drug efflux is a potential mechanism of resistance to imatinib [45, 46].…”

“…Nevertheless, researchers agree that expression levels of ABCB1 are strong predictors of imatinib responsiveness [43, 44] and could be monitored as early response markers in CML patients receiving imatinib [58]. …”