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
References
Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9–29.
Theillet C. What do we learn from HER2-positive breast cancer genomic profiles? Breast Cancer Res. 2010;12:107.
Huw LY, O'Brien C, Pandita A, Mohan S, Spoerke JM, Lu S, et al. Acquired PIK3CA amplification causes resistance to selective phosphoinositide 3-kinase inhibitors in breast cancer. Oncogenesis. 2013;2:e83.
Jerjees DA, Alabdullah M, Green AR, Alshareeda A, Macmillan RD, Ellis IO, et al. Prognostic and biological significance of proliferation and HER2 expression in the luminal class of breast cancer. Breast Cancer Res Treat. 2014;145:317–30.
Takada M, Ishiguro H, Nagai S, Ohtani S, Kawabata H, Yanagita Y, et al. Survival of HER2-positive primary breast cancer patients treated by neoadjuvant chemotherapy plus trastuzumab: a multicenter retrospective observational study (JBCRG-C03 study). Breast Cancer Res Treat. 2014;145:143–53.
Valachis A, Nearchou A, Lind P, Mauri D. Lapatinib, trastuzumab or the combination added to preoperative chemotherapy for breast cancer: a meta-analysis of randomized evidence. Breast Cancer Res Treat. 2012;135:655–62.
Higa GM, Abraham J. Lapatinib in the treatment of breast cancer. Expert Rev Anticancer Ther. 2007;7:1183–92.
Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006;355:2733–43.
Lin NU, Dieras V, Paul D, Lossignol D, Christodoulou C, Stemmler HJ, et al. Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin Cancer Res. 2009;15:1452–9.
Browne BC, O'Brien N, Duffy MJ, Crown J, O'Donovan N. HER-2 signaling and inhibition in breast cancer. Curr Cancer Drug Targets. 2009;9:419–38.
Gomez HL, Doval DC, Chavez MA, Ang PC, Aziz Z, Nag S, et al. Efficacy and safety of lapatinib as first-line therapy for ErbB2-amplified locally advanced or metastatic breast cancer. J Clin Oncol. 2008;26:2999–3005.
Liu L, Greger J, Shi H, Liu Y, Greshock J, Annan R, et al. Novel mechanism of lapatinib resistance in HER2-positive breast tumor cells: activation of AXL. Cancer Res. 2009;69:6871–8.
Wang Q, Quan H, Zhao J, **e C, Wang L, Lou L. RON confers lapatinib resistance in HER2-positive breast cancer cells. Cancer Lett. 2013;340:43–50.
Chen CT, Kim H, Liska D, Gao S, Christensen JG, Weiser MR. MET activation mediates resistance to lapatinib inhibition of HER2-amplified gastric cancer cells. Mol Cancer Ther. 2012;11:660–9.
Formisano L, Nappi L, Rosa R, Marciano R, D'Amato C, D'Amato V, et al. Epidermal growth factor-receptor activation modulates Src-dependent resistance to lapatinib in breast cancer models. Breast Cancer Res. 2014;16:R45.
Brady SW, Zhang J, Seok D, Wang H, Yu D. Enhanced PI3K p110alpha signaling confers acquired lapatinib resistance that can be effectively reversed by a p110alpha-selective PI3K inhibitor. Mol Cancer Ther. 2014;13:60–70.
Qadir MA, Kwok B, Dragowska WH, To KH, Le D, Bally MB, et al. Macroautophagy inhibition sensitizes tamoxifen-resistant breast cancer cells and enhances mitochondrial depolarization. Breast Cancer Res Treat. 2008;112:389–403.
Chen S, Rehman SK, Zhang W, Wen A, Yao L, Zhang J. Autophagy is a therapeutic target in anticancer drug resistance. Biochim Biophys Acta. 1806;2010:220–9.
Sui X, Chen R, Wang Z, Huang Z, Kong N, Zhang M, et al. Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment. Cell Death Dis. 2013;4:e838.
Zhu X, Wu L, Qiao H, Han T, Chen S, Liu X, et al. Autophagy stimulates apoptosis in HER2-overexpressing breast cancers treated by lapatinib. J Cell Biochem. 2013;114:2643–53.
Eskelinen EL, Reggiori F, Baba M, Kovacs AL, Seglen PO. Seeing is believing: the impact of electron microscopy on autophagy research. Autophagy. 2011;7:935–56.
Kuma A, Matsui M, Mizushima N. LC3, an autophagosome marker, can be incorporated into protein aggregates independent of autophagy: caution in the interpretation of LC3 localization. Autophagy. 2007;3:323–8.
Robidoux A, Tang G, Rastogi P, Geyer Jr CE, Azar CA, Atkins JN, et al. Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial. Lancet Oncol. 2013;14:1183–92.
De Luca A, D'Alessio A, Gallo M, Maiello MR, Bode AM, Normanno N. Src and CXCR4 are involved in the invasiveness of breast cancer cells with acquired resistance to lapatinib. Cell Cycle. 2014;13:148–56.
**e CM, Liu XY, Sham KW, Lai JM, Cheng CH. Silencing of EEF2K (eukaryotic elongation factor-2 kinase) reveals AMPK-ULK1-dependent autophagy in colon cancer cells. Autophagy 2014;10.
Otomo C, Metlagel Z, Takaesu G, Otomo T. Structure of the human ATG12∼ATG5 conjugate required for LC3 lipidation in autophagy. Nat Struct Mol Biol. 2013;20:59–66.
Gibbings D, Mostowy S, Jay F, Schwab Y, Cossart P, Voinnet O. Selective autophagy degrades DICER and AGO2 and regulates miRNA activity. Nat Cell Biol. 2012;14:1314–21.
Kovaleva V, Mora R, Park YJ, Plass C, Chiramel AI, Bartenschlager R, et al. miRNA-130a targets ATG2B and DICER1 to inhibit autophagy and trigger killing of chronic lymphocytic leukemia cells. Cancer Res. 2012;72:1763–72.
Yu DH, Zhang X, Wang H, Zhang L, Chen H, Hu M, et al. The essential role of TNIK gene amplification in gastric cancer growth. Oncogenesis. 2014;2:e89.
Shacka JJ, Klocke BJ, Roth KA. Autophagy, bafilomycin and cell death: the “a-B-cs” of plecomacrolide-induced neuroprotection. Autophagy. 2006;2:228–30.
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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Suning Chen, **ngmei 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