Tyrosine kinase inhibitor resistance in chronic myeloid leukemia cell lines: investigating resistance pathways

Autor:	Deborah L. White, Timothy P. Hughes, Dale B. Watkins, Sarah Moore, Carine Tang, Wendy T Parker, Lisa Schafranek, Jodi Prime
Přispěvatelé:	Tang, Carine, Schafranek, Lisa, Watkins, Dale, Parker, Wendy, Moore, Sarah, Prime, Jodi, White, Deborah, Hughes, Timothy P
Rok vydání:	2011
Předmět:	Cancer Research Dasatinib Fusion Proteins bcr-abl cell lines and animal models Piperazines Tyrosine-kinase inhibitor hemic and lymphatic diseases ATP Binding Cassette Transporter Subfamily G Member 2 Phosphorylation In Situ Hybridization Fluorescence Reverse Transcriptase Polymerase Chain Reaction Nuclear Proteins Myeloid leukemia Hematology Flow Cytometry Neoplasm Proteins Gene Expression Regulation Neoplastic Leukemia Oncology Benzamides Imatinib Mesylate Tyrosine kinase medicine.drug ATP Binding Cassette Transporter Subfamily B medicine.drug_class Blotting Western Antineoplastic Agents Biology Inhibitory Concentration 50 Cell Line Tumor Leukemia Myelogenous Chronic BCR-ABL Positive medicine Humans ATP Binding Cassette Transporter Subfamily B Member 1 Protein Kinase Inhibitors neoplasms Adaptor Proteins Signal Transducing drug resistance Dose-Response Relationship Drug Imatinib medicine.disease Virology myeloid leukemias and dysplasias Thiazoles Pyrimidines Imatinib mesylate Nilotinib Drug Resistance Neoplasm Mutation Cancer research ATP-Binding Cassette Transporters K562 Cells
Zdroj:	Leukemia & Lymphoma. 52:2139-2147
ISSN:	1029-2403 1042-8194
DOI:	10.3109/10428194.2011.591013
Popis:	There are three currently identified secondary resistance mechanisms observed in patients with chronic myeloid leukemia (CML) receiving tyrosine kinase inhibitors (TKIs). These are BCR-ABL kinase domain (KD) mutations, increased BCR-ABL expression, and overexpression of drug-efflux proteins (ABCB1 and ABCG2). To investigate the interplay between these three modes of resistance, three CML blast crisis cell lines (K562, its ABCB1-overexpressing variant K562 Dox, and KU812) were cultured in gradually increasing concentrations of imatinib to 2 mu M, or dasatinib to 200 nM. Eight imatinib-and two dasatinib-resistant cell lines were established. Two imatinib-resistant K562 lines both had increased BCR-ABL expression as the apparent mode of resistance. However, when a dasatinib-resistant K562 culture was generated we observed gradually increasing BCR-ABL expression which peaked prior to identification of the T315I mutation. BCR-ABL overexpression followed by mutation development was observed in a further 4/10 cell lines, each with different KD mutations. In contrast, three imatinib-resistant K562 Dox lines exhibited only a further increase in ABCB1 expression. All TKI-resistant cell lines generated had increased IC(50) (dose of drug required to reduce phosphorylation of the adaptor protein p-Crkl by 50%) to imatinib, dasatinib, and nilotinib, regardless of which TKI was used to induce resistance. This suggests that currently available TKIs share the same susceptibilities to drug resistance. Refereed/Peer-reviewed
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b40c876b351459425198e4bff6f18632 https://doi.org/10.3109/10428194.2011.591013 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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