Drug transporters play a key role in the complex process of Imatinib resistance in vitro

Alves, Raquel; Figueiredo, A.; Gonçalves, Ana Cristina; Ferreira-Teixeira, Margarida; Lima, Joana Esteves de; Abrantes, Ana Margarida; Alves, Vera; Rodrigues-Santos, Paulo; Jorge, Lénia; Matoso, Eunice; Carreira, Isabel M.; Botelho, Maria Filomena; Sarmento‐Ribeiro, Ana Bela

doi:10.1016/j.leukres.2014.12.008

Cited by 20 publications

(19 citation statements)

References 26 publications

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“…The sensitive cell line was obtained from ATCC, and the Imatinib-resistant cell lines were developed in our laboratory based on two strategies: a continuous exposure (K562-RC) and a discontinuous exposure to Imatinib (K562-RD), as described in Alves et al . 40 .…”

Section: Methodsmentioning

confidence: 99%

MicroRNA signature refine response prediction in CML

Alves

Gonçalves

Jorge

et al. 2019

Sci Rep

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microRNAs (miRs) dysregulation have emerged as a crucial step in tumorigenesis, being related with cancer development, progression and response to treatment. In chronic myeloid leukaemia (CML), the resistance to tyrosine kinase inhibitors (TKI) is responsible for treatment failure and could be linked to changes in miRs expression. This work aimed to correlate the expression levels of 3 miRs, miR-21, miR-26b and miR-451, with response to TKI treatment in CML patients. miR-451 levels at diagnosis were significantly higher in patients with optimal response after 6 and 12 months of therapy. Conversely, patients without optimal response had highest levels of miR-21. miR-21 and miR-451 appear to be good biomarkers of response, able to predict optimal TKI responders (p < 0.05). Using the combined profile of both miRs, we create a predictive model of optimal response after one year of treatment. This study highlights the role of miR-21 and miR-451 expression levels at diagnosis in predicting which patients achieve the optimal response.

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Section: Methodsmentioning

confidence: 99%

MicroRNA signature refine response prediction in CML

Alves

Gonçalves

Jorge

et al. 2019

Sci Rep

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“…Low expression of these transporters induced a reduction of TKIs cytosolic concentrations, playing an important role in therapeutic failure . The expression profile of influx carriers was significantly decreased in imatinib‐resistant cell lines (i.e., K562‐RC) with respect to the parental K562 cell line . Although those data strengthened the role of transporters in response or resistance to TKIs, the correlation among transporters, LSCs and TKIs resistance has not yet been described.…”

Section: Introductionmentioning

confidence: 94%

Concise Review: Chronic Myeloid Leukemia: Stem Cell Niche and Response to Pharmacologic Treatment

Arrigoni

Galimberti

et al. 2018

Stem Cells Translational Medicine

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Nowadays, more than 90% of patients affected by chronic myeloid leukemia (CML) survive with a good quality of life, thanks to the clinical efficacy of tyrosine kinase inhibitors (TKIs). Nevertheless, point mutations of the ABL1 pocket occurring during treatment may reduce binding of TKIs, being responsible of about 20% of cases of resistance among CML patients. In addition, the presence of leukemic stem cells (LSCs) represents the most important event in leukemia progression related to TKI resistance. LSCs express stem cell markers, including active efflux pumps and genetic and epigenetic alterations together with deregulated cell signaling pathways involved in self‐renewal, such as Wnt/β‐catenin, Notch, and Hedgehog. Moreover, the interaction with the bone marrow microenvironment, also known as hematopoietic niche, may influence the phenotype of surrounding cells, which evade mechanisms controlling cell proliferation and are less sensitive or frankly resistant to TKIs. This Review focuses on the role of LSCs and stem cell niche in relation to response to pharmacological treatments. A literature search from PubMed database was performed until April 30, 2017, and it has been analyzed according to keywords such as chronic myeloid leukemia, stem cell, leukemic stem cells, hematopoietic niche, tyrosine kinase inhibitors, and drug resistance. Stem Cells Translational Medicine 2018;7:305–314

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“…Harrach et al proposed that measurement of MATE1 expression levels before treatment can help in identifying Imatinib non-responder patients [ 86 ]. In Imatinib-resistant cell lines, Alves et al observed a parallel decrease in OCT1 and OCTN2 expression showing the contribution of more than one influx transporters to the resistance process [ 87 ]. Lower levels of TKI uptake could be overcome with a switch to Dasatinib since this TKI can cross the cell membrane by diffusion [ 88 , 89 ].…”

Section: Molecular Mechanismsmentioning

confidence: 99%

Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia—From Molecular Mechanisms to Clinical Relevance

Alves

Gonçalves

Rutella

et al. 2021

Cancers

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Resistance to targeted therapies is a complex and multifactorial process that culminates in the selection of a cancer clone with the ability to evade treatment. Chronic myeloid leukemia (CML) was the first malignancy recognized to be associated with a genetic alteration, the t(9;22)(q34;q11). This translocation originates the BCR-ABL1 fusion gene, encoding the cytoplasmic chimeric BCR-ABL1 protein that displays an abnormally high tyrosine kinase activity. Although the vast majority of patients with CML respond to Imatinib, a tyrosine kinase inhibitor (TKI), resistance might occur either de novo or during treatment. In CML, the TKI resistance mechanisms are usually subdivided into BCR-ABL1-dependent and independent mechanisms. Furthermore, patients’ compliance/adherence to therapy is critical to CML management. Techniques with enhanced sensitivity like NGS and dPCR, the use of artificial intelligence (AI) techniques, and the development of mathematical modeling and computational prediction methods could reveal the underlying mechanisms of drug resistance and facilitate the design of more effective treatment strategies for improving drug efficacy in CML patients. Here we review the molecular mechanisms and other factors involved in resistance to TKIs in CML and the new methodologies to access these mechanisms, and the therapeutic approaches to circumvent TKI resistance.

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Drug transporters play a key role in the complex process of Imatinib resistance in vitro

Cited by 20 publications

References 26 publications

MicroRNA signature refine response prediction in CML

MicroRNA signature refine response prediction in CML

Concise Review: Chronic Myeloid Leukemia: Stem Cell Niche and Response to Pharmacologic Treatment

Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia—From Molecular Mechanisms to Clinical Relevance

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