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Volume 21
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10.3390/molecules21091236
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Article

Osimertinib (AZD9291), a Mutant-Selective EGFR Inhibitor, Reverses ABCB1-Mediated Drug Resistance in Cancer Cells

by
Xiao-Yu Zhang
1,
Yun-Kai Zhang
1,
Yi-Jun Wang
1,
Pranav Gupta
1,
Leli Zeng
1,2,
Megan Xu
1,†,
Xiu-Qi Wang
3,
Dong-Hua Yang
1 and
Zhe-Sheng Chen
1,*
1
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY 11439, USA
2
School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, China
3
College of Animal Science, South China Agricultural University, Guangzhou 510642, China
*
Author to whom correspondence should be addressed.
Molecules 2016, 21(9), 1236; https://doi.org/10.3390/molecules21091236
Submission received: 18 June 2016 / Revised: 7 September 2016 / Accepted: 10 September 2016 / Published: 15 September 2016
(This article belongs to the Special Issue New Approaches to Counteract Drug Resistance in Cancer)
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Abstract

In recent years, tyrosine kinase inhibitors (TKIs) have been shown capable of inhibiting the ATP-binding cassette (ABC) transporter-mediated multidrug resistance (MDR). In this study, we determine whether osimertinib, a novel selective, irreversible EGFR (epidermal growth factor receptor) TKI, could reverse ABC transporter-mediated MDR. The results showed that, at non-toxic concentrations, osimertinib significantly sensitized both ABCB1-transfected and drug-selected cell lines to substrate anticancer drugs colchicine, paclitaxel, and vincristine. Osimertinib significantly increased the accumulation of [3H]-paclitaxel in ABCB1 overexpressing cells by blocking the efflux function of ABCB1 transporter. In contrast, no significant alteration in the expression levels and localization pattern of ABCB1 was observed when ABCB1 overexpressing cells were exposed to 0.3 µM osimertinib for 72 h. In addition, ATPase assay showed osimertinib stimulated ABCB1 ATPase activity. Molecular docking and molecular dynamic simulations showed osimertinib has strong and stable interactions at the transmembrane domain of human homology ABCB1. Taken together, our findings suggest that osimertinib, a clinically-approved third-generation EGFR TKI, can reverse ABCB1-mediated MDR, which supports the combination therapy with osimertinib and ABCB1 substrates may potentially be a novel therapeutic stategy in ABCB1-positive drug resistant cancers.
Keywords: osimertinib; multidrug resistance; ABCB1; tyrosine kinase inhibitors osimertinib; multidrug resistance; ABCB1; tyrosine kinase inhibitors

Share and Cite

MDPI and ACS Style

Zhang, X.-Y.; Zhang, Y.-K.; Wang, Y.-J.; Gupta, P.; Zeng, L.; Xu, M.; Wang, X.-Q.; Yang, D.-H.; Chen, Z.-S. Osimertinib (AZD9291), a Mutant-Selective EGFR Inhibitor, Reverses ABCB1-Mediated Drug Resistance in Cancer Cells. Molecules 2016, 21, 1236. https://doi.org/10.3390/molecules21091236

AMA Style

Zhang X-Y, Zhang Y-K, Wang Y-J, Gupta P, Zeng L, Xu M, Wang X-Q, Yang D-H, Chen Z-S. Osimertinib (AZD9291), a Mutant-Selective EGFR Inhibitor, Reverses ABCB1-Mediated Drug Resistance in Cancer Cells. Molecules. 2016; 21(9):1236. https://doi.org/10.3390/molecules21091236

Chicago/Turabian Style

Zhang, Xiao-Yu, Yun-Kai Zhang, Yi-Jun Wang, Pranav Gupta, Leli Zeng, Megan Xu, Xiu-Qi Wang, Dong-Hua Yang, and Zhe-Sheng Chen. 2016. "Osimertinib (AZD9291), a Mutant-Selective EGFR Inhibitor, Reverses ABCB1-Mediated Drug Resistance in Cancer Cells" Molecules 21, no. 9: 1236. https://doi.org/10.3390/molecules21091236

APA Style

Zhang, X.-Y., Zhang, Y.-K., Wang, Y.-J., Gupta, P., Zeng, L., Xu, M., Wang, X.-Q., Yang, D.-H., & Chen, Z.-S. (2016). Osimertinib (AZD9291), a Mutant-Selective EGFR Inhibitor, Reverses ABCB1-Mediated Drug Resistance in Cancer Cells. Molecules, 21(9), 1236. https://doi.org/10.3390/molecules21091236

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