The Genomic Stability at the Coding Regions of the Multidrug Transporter Gene ABCB1: Insights into the Development of Alternative Drug Resistance Mechanisms in Human Leukemia Cells

Despite considerable efforts in reversing clinical multidrug resistance (MDR), targeting the predominant multidrug transporter ABCB1/P-glycoprotein (P-gp) based on small molecule inhibitors has been hindered. This may be due to the emergence of alternative drug resistance mechanisms. However, the no...

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Published inbioRxiv
Main Authors Chen, Kevin G, Duran, George E, Mogul, Mark J, Wang, Yan C, Ross, Kevin L, Jaffrezou, Jean-Pierre, Huff, Lyn M, Fojo, Tito, Lacayo, Norman J, Sikic, Branimir I
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 28.10.2019
Subjects
ABC transporter
ABCA1 protein
Acute myeloid leukemia
ATP-binding protein
Cyclosporins
Doxorubicin
Drug resistance
Erythroleukemia
Etoposide
Leukemia
Multidrug resistance
Myeloid leukemia
P-Glycoprotein
Patients
Phenotypes
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Summary:Despite considerable efforts in reversing clinical multidrug resistance (MDR), targeting the predominant multidrug transporter ABCB1/P-glycoprotein (P-gp) based on small molecule inhibitors has been hindered. This may be due to the emergence of alternative drug resistance mechanisms. However, the non-specific P-gp inhibitor cyclosporine (CsA) showed significant clinical benefits in patients with acute myeloid leukemia (AML), which likely represents the only proof-of-principle clinical trial using several generations of MDR inhibitors. Nevertheless, the mechanisms that underlie this successful MDR modulation by CsA are not elucidated because of the absence of CsA-relevant cellular models. In this study, we report the development of two erythroleukemia variants, RVC and RDC, which were derived by step-wise co-selection of K562/R7 drug-resistant leukemia cells with the etoposide-CsA and doxorubicin-CsA drug combinations, respectively. Interestingly, both RVC and RDC, which retained P-gp expression, showed altered MDR phenotypes that were resistant to cyclosporine modulation. The ABCB1 coding regions were genetically stable even under long-term stringent drug selection. Genomically, ABCB1 is likely the most stable ABC transporter gene when comparing with several ABC superfamily members (such as ABCA1, ABCC1, CFTR, and ABCG2). Our findings suggested that non-P-gp mechanisms were likely responsible for the resistance to CsA modulation in both RVC and RDC cells. Moreover, we found that CsA played a role in undermining the selection of highly drug-resistant cells via induction of low level and unstable drug resistance, thus shedding some light on the benefits of CsA in treating certain types of AML patients.
DOI:10.1101/820639