Instability of mRNA expression signatures of drug transporters in chronic myeloid leukemia patients resistant to imatinib

Abstract

Despite the success of imatinib mesylate (IM) in the treatment of chronic myeloid leukemia (CML), approximately 30% of patients are resistant to therapy, mostly due to unknown causes. To profile the expression signatures of drug transporters throughout IM therapy and correlate them with resistance, we quantified mRNA expression levels of the SLC22A12, ABCB1, ABCC1, ABCG2 and MVP genes in consecutive samples from peripheral blood or bone marrow of CML patients who were either responsive or resistant to IM. Additionally we identified and quantified BCR-ABL1 transcript variants and analyzed 1236T>C ABCB1 and 480G>C SLC22A1 polymorphisms. A relationship between the type of BCR-ABL1 transcript or ABCB1 or SLC22A1 genotype and response to treatment was not discovered. However, the studied genes had higher expression levels in follow-up compared to the diagnostic samples, demonstrating a possible induction in expression. IM-sensitive patients presented significantly higher values of SLC22A1 expression, suggesting higher drug influx. Most importantly, while responding patients demonstrated stable expression signatures in consecutive samples, there was considerable variation in IM-resistant patients, indicating that single point sampling expression signatures are not reliable in predicting clinical outcomes or prognostic features in these patients. Studies that assessed consecutive samples from CML patients in order to evaluate the variation in expression levels of transporter genes are limited yet our study emphasizes the importance of such approaches.

ABC Efflux Transporters and the Circuitry of miRNAs: Kinetics of Expression in Cancer Drug Resistance

“…However, as acquired CDR is a time-dependent process, the assessment of the mechanisms that are activated as cells to develop resistance is critical. One interesting phenomenon that we were able to identify in a model of chronic myeloid leukemia was the sequential activation of different ABC transporter expressions (ABCB1, ABCG2, ABCC1), as cells gained resistance to the tyrosine kinase inhibitor Imatinib [9], and the relatively unstable pattern of expression of these transporters in human samples [28]. These observations indicated that the time-dependent analysis of CDR is critical to a better understanding of the mechanisms involved.…”

“…Several groups have developed cell lines resistant to specific cancer drugs, such as doxorubicin, or paclitaxel, to study biomarkers of CDR [25,26]. However, the time course of occurrence of resistance mechanisms has not always been possible to assess and is not yet generally known and understood [9,27,28]. Furthermore, another issue that has not been addressed is the mechanism underlying the loss of resistance to therapy once the challenge to these cells is withdrawn.…”

Genotypes of SLC22A4 and SLC22A5 regulatory loci are predictive of the response of chronic myeloid leukemia patients to imatinib treatment

“…Major molecular response (MMR, i.e., ≤0.1% BCR-ABL1 IS ; IS – International Scale) is frequently observed during imatinib treatment regardless of the daily dose in patients with increased SLC22A1 (OCT1) activity. Patients with normal or reduced activity of this transporter benefit from an increase in the imatinib dose and achieve MMR more frequently than patients who received standard doses [9, 10]. …”

Role of SLC22A1 polymorphic variants in drug disposition, therapeutic responses, and drug–drug interactions

“…However, a further study in a smaller cohort of 33 patients showed no correlation between this polymorphic variant and response to treatment. 60 All studies involving the R61C variant showed no correlation between its occurrence in patients and response to imatinib. [61][62][63][64] Otherwise, patients carrying the G401S variant showed high probability of achieving major molecular response to the drug.…”