Abstract
The introduction of imatinib (IM), a BCR-ABL1 tyrosine kinase inhibitor (TKI), has represented a significant advance in the first-line treatment of chronic myeloid leukemia (CML). However, approximately 30% of patients need to discontinue IM due to resistance or intolerance to this drug. Both resistance and intolerance have also been observed in treatment with the second-generation TKIs—dasatinib, nilotinib, and bosutinib—and the third-generation TKI—ponatinib. The mechanisms of resistance to TKIs may be BCR-ABL1-dependent and/or BCR-ABL1-independent. Although the role of efflux pump P-glycoprotein (Pgp), codified by the ABCB1 gene, is unquestionable in drug resistance of many neoplasms, a longstanding question exists about whether Pgp has a firm implication in TKI resistance in the clinical scenario. The goal of this review is to offer an overview of ABCB1/Pgp expression/activity/polymorphisms in CML. Understanding how interactions, associations, or cooperation between Pgp and other molecules—such as inhibitor apoptosis proteins, microRNAs, or microvesicles—impact IM resistance risk may be critical in evaluating the response to TKIs in CML patients. In addition, new non-TKI compounds may be necessary in order to overcome the resistance mediated by Pgp in CML.
Highlights
Understanding how interactions, associations, or cooperation between Pgp and other molecules—such as inhibitor apoptosis proteins, microRNAs, or microvesicles—impact Imatinib mesylate (IM) resistance risk may be critical in evaluating the response to tyrosine kinase inhibitor (TKI) in chronic myeloid leukemia (CML) patients
Chronic myeloid leukemia (CML) is a form of hematopoietic stem cell disease characterized by the presence of the oncogene BCR-ABL, which is created by the fusion of BCR and ABL genes and results in a constitutively active BCR-ABL tyrosine kinase protein [1]
This study indicates that early monitoring using ABCB1 mRNA levels may represent an accessible marker for predicting early response or resistance to IM and nilotinib, which are both Pgp substrates [50,51]
Summary
Chronic myeloid leukemia (CML) is a form of hematopoietic stem cell disease characterized by the presence of the oncogene BCR-ABL, which is created by the fusion of BCR and ABL genes and results in a constitutively active BCR-ABL tyrosine kinase protein [1]. This protein stimulates a number of cell survival signaling pathways, such as the PI3K/AKT/mTOR and RAS/RAF/MEK/ERK pathways, resulting in uncontrolled proliferation and apoptosis inhibition [2,3]. IM is widely used around the world as first-line treatment for CML patients. More potent second-generation TKIs—such as dasatinib, nilotinib, bosutinib, and ponatinib [8,9,10,11]—do not overcome resistance or side effects [12,13] in all patients
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
