Research Papers:

Afatinib circumvents multidrug resistance via dually inhibiting ATP binding cassette subfamily G member 2 in vitro and in vivo

Xiao-kun Wang _, Kenneth Kin Wah To, Li-yan Huang, Jing-hong Xu, Ke Yang, Fang Wang, Zhen-cong Huang, Sheng Ye and Li-wu Fu

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Oncotarget. 2014; 5:11971-11985. https://doi.org/10.18632/oncotarget.2647

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Xiao-kun Wang1, Kenneth Kin Wah To2, Li-yan Huang1, Jing-hong Xu3, Ke Yang1, Fang Wang1, Zhen-cong Huang1, Sheng Ye3, Li-wu Fu1

1State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China

2School of Pharmacy, The Chinese University of Hong Kong, Hong Kong, P.R. China

3First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China

Correspondence to:

Li-wu Fu, e-mail: [email protected]

Keywords: Multidrug resistance, ABCG2, tyrosine kinase inhibitor, afatinib, combined chemotherapy

Received: July 05, 2014     Accepted: October 27, 2014     Published: November 24, 2014


Multidrug resistance (MDR) to chemotherapeutic drugs is a formidable barrier to the success of cancer chemotherapy. Expressions of ATP-binding cassette (ABC) transporters contribute to clinical MDR phenotype. In this study, we found that afatinib, a small molecule tyrosine kinase inhibitor (TKI) targeting EGFR, HER-2 and HER-4, reversed the chemoresistance mediated by ABCG2 in vitro, but had no effect on that mediated by multidrug resistance protein ABCB1 and ABCC1. In addition, afatinib, in combination with topotecan, significantly inhibited the growth of ABCG2- overexpressing cell xenograft tumors in vivo. Mechanistic investigations exhibited that afatinib significantly inhibited ATPase activity of ABCG2 and downregulated expression level of ABCG2, which resulted in the suppression of efflux activity of ABCG2 in parallel to the increase of intracellular accumulation of ABCG2 substrate anticancer agents. Taken together, our findings may provide a new and useful combinational therapeutic strategy of afatinib with chemotherapeutical drug for the patients with ABCG2 overexpressing cancer cells.

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