Open AccessGenomic stability at the coding regions of the multidrug transporter gene ABCB1: insights into the development of alternative drug resistance mechanisms in human leukemia cells
Author(s) -
Kevin G. Chen,
George E. Durán,
Mark Mogul,
Yan C. Wang,
Kevin L. Ross,
JeanPierre Jaffrézou,
Lyn M. Huff,
Kory R. Johnson,
Tito Fojo,
Norman J. Lacayo,
Branimir I. Šikić
Publication year - 2020
Publication title -
cancer drug resistance (alhambra, calif.)
Language(s) - English
Resource type - Journals
eISSN - 2578-532X
DOI - 10.20517/cdr.2020.51
Subject(s) - multiple drug resistance , biology , drug resistance , myeloid leukemia , etoposide , drug , leukemia , cancer research , pharmacology , genetics , chemotherapy
Despite considerable efforts to reverse clinical multidrug resistance (MDR), targeting the predominant multidrug transporter ABCB1/P-glycoprotein (P-gp) using small molecule inhibitors has been unsuccessful, possibly 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 mutational mechanisms that may underlie unsuccessful MDR modulation by CsA are not elucidated because of the absence of CsA-relevant cellular models. In this study, our aims were to establish CsA-resistant leukemia models and to examine the presence or absence of ABCB1 exonic mutations in these models as well as in diverse types of human cancer samples including AMLs.