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Protective autophagy promotes the resistance of HER2-positive breast cancer cells to lapatinib

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Tumor Biology

Abstract

Lapatinib, a tyrosine kinase inhibitor of HER2/EGFR, can inhibit the proliferation of HER2-positive breast cancer cells. Additionally, the combination of lapatinib and chemotherapy can markedly prolong patient survival time. However, the clinical therapeutic effect of lapatinib is severely limited by drug resistance. We previously found that brief treatment with lapatinib induced both apoptosis and autophagy in HER2-positive breast cancer cells. Additionally, the apoptosis induced by lapatinib was dependent on autophagy. In our current study, however, we used extended treatment of HER2-positive breast cancer cells with lapatinib to confirm the presence of protective autophagy in the previously established lapatinib-resistant cells. Specifically, we found that inhibition of autophagy could reduce the proliferation, DNA synthesis, and colony-forming capacity of resistant cells. Thus, autophagy is a potential novel therapeutic target for reversing lapatinib resistance of HER2-positive breast cancer cells. Our data provide clear, novel evidence of both anti-apoptotic and pro-apoptotic functions of autophagy in breast cancer during lapatinib treatment.

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Abbreviations

BT-474par :

Parental BT-474 cells

BT-474LapR :

Lapatinib-resistant BT-474 cells

AU-565par :

Parental AU-565 cells

AU-565LapR :

Lapatinib-resistant AU-565 cells

HER2:

Human epidermal growth factor receptor 2

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Acknowledgments

This study was supported by the National Natural Science Foundation of China (81202091, 81402186, and 81102006) and the Natural Science Foundation of Shaanxi Province (2013JC2-21).

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    Authors and Affiliations

    1. Department of Pharmacy, Xijing Hospital, The Fourth Military Medical University, Xi’an, Shaanxi, 710032, China

      Suning Chen, Likun Ding & Aidong Wen

    2. The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, No. 169 Changle West Road, Xi’an, Shaanxi, 710032, China

      Xingmei Zhu, Hongyu Qiao, Mingxiang Ye, Xiaofeng Lai & Jian Zhang

    3. Department of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, 712046, China

      Xingmei Zhu

    4. Cadet Brigade of the Fourth Military Medical University, The Fourth Military Medical University, Xi’an, 710032, China

      Shentong Yu

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    1. Suning Chen
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    Correspondence to Aidong Wen or Jian Zhang.

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    Suning Chen, Xingmei Zhu and Hongyu Qiao contributed equally to this work.

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    Chen, S., Zhu, X., Qiao, H. et al. Protective autophagy promotes the resistance of HER2-positive breast cancer cells to lapatinib. Tumor Biol. 37, 2321–2331 (2016). https://doi.org/10.1007/s13277-015-3800-9

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    • DOI: https://doi.org/10.1007/s13277-015-3800-9

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