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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2018.01312

ABCC10 plays a significant role in the transport of gefitinib and contributes to acquired resistance to gefitinib in NSCLC

Hongbo Zhao1, Yutang Huang2, Jingjing Shi2, Yi Dai2,  Lanxiang Wu2* and Honghao Zhou3
  • 1Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, China
  • 2Institute of Life Sciences, Chongqing Medical University, China
  • 3Pharmacogenetics Research Institute, Institute of Clinical Pharmacology, Central South University, China

Gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is used clinically as first-line therapy in patients with advanced non-small cell lung cancer (NSCLC) with EGFR activating mutations, but the inevitable development of acquired resistance limits its efficacy. In up to 30-40% of NSCLC cases, the mechanism underlying acquired resistance remains unknown. ATP-binding cassette (ABC) transporters are a family of membrane proteins that can significantly influence the bioavailability of numerous drugs, and have confirmed to play an essential role in multidrug resistance (MDR) in cancer chemotherapy. However, their role in acquired resistance to gefitnib in NSCLC has not been well studied. Here, through RNA sequencing (RNA-Seq) technology we assessed the differentially expressed ABC transporters in gefitinib-sensitive (PC9 and H292) and gefitinib-resistant (PC9/GR and H292/GR) NSCLC cells, with ABCC10 identified as a transporter of interest. Both ABCC10 mRNA and protein were significantly increased in acquired gefitinib-resistant NSCLC cells, independent of EGFR mutation status. In vitro transport assay showed that ABCC10 could actively efflux gefitinib, with an efflux ratio (ER) of 7.8. Further results from in vitro cell line models and in vivo xenograft models showed that overexpression of ABCC10 led to a reduction in gefitinib sensitivity through decreasing the intracellular gefitinib accumulation. Our data suggest that ABCC10 has an important role in acquired resistance to gefitinib in NSCLC, which can serve as a novel predictive marker and a potential therapeutic target in gefitinib treatment.

Keywords: ABC transporter, ABCC10, gefitinib, acquired resistance, Non-small cell lung cancer

Received: 04 Sep 2018; Accepted: 29 Oct 2018.

Edited by:

Petr Pavek, Charles University, Czechia

Reviewed by:

Cesare Indiveri, Università della Calabria, Italy
Zhihao Liu, University of Illinois at Chicago, United States  

Copyright: © 2018 Zhao, Huang, Shi, Dai, Wu and Zhou. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Lanxiang Wu, Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, China, lxwu2008@126.com