NF-κB activation-induced anti-apoptosis renders HER2-positive cells drug resistant and accelerates tumor growth

Shannon T. Bailey, Penelope L. Miron, Yoon J. Choi, Bose Kochupurakkal, Gautam Maulik, Scott J. Rodig, Ruiyang Tian, Kathleen M. Foley, Teresa Bowman, Alexander Miron, Myles Brown, J. Dirk Iglehart, Debajit K. Biswas

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27 Scopus citations

Abstract

Breast cancers with HER2 overexpression are sensitive to drugs targeting the receptor or its kinase activity. HER2-targeting drugs are initially effective against HER2-positive breast cancer, but resistance inevitably occurs. We previously found that NF-κB is hyperactivated in a subset of HER2-positive breast cancer cells and tissue specimens. In this study, we report that constitutively active NF-κB rendered HER2-positive cancer cells resistant to anti-HER2 drugs and cells selected for lapatinib resistance upregulated NF-κB. In both circumstances, cells were antiapoptotic and grew rapidly as xenografts. Lapatinib-resistant cells were refractory to HER2 and NF-κB inhibitors alone but were sensitive to their combination, suggesting a novel therapeutic strategy. A subset of NF-κB-responsive genes was overexpressed in HER2-positive and triple-negative breast cancers, and patients with this NF-κB signature had poor clinical outcome. Anti-HER2 drug resistance may be a consequence of NF-κB activation, and selection for resistance results in NF-κB activation, suggesting that this transcription factor is central to oncogenesis and drug resistance. Clinically, the combined targeting of HER2 and NF-κB suggests a potential treatment paradigm for patients who relapse after anti-HER2 therapy. Patients with these cancers may be treated by simultaneously suppressing HER2 signaling and NF-κB activation. Implications: The combination of an inhibitor of Ik B kinase (IKK) inhibitor and anti-HER2 drugs may be a novel treatment strategy for drug-resistant human breast cancers.

Original languageEnglish (US)
Pages (from-to)408-420
Number of pages13
JournalMolecular Cancer Research
Volume12
Issue number3
DOIs
StatePublished - Mar 2014

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ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Bailey, S. T., Miron, P. L., Choi, Y. J., Kochupurakkal, B., Maulik, G., Rodig, S. J., Tian, R., Foley, K. M., Bowman, T., Miron, A., Brown, M., Iglehart, J. D., & Biswas, D. K. (2014). NF-κB activation-induced anti-apoptosis renders HER2-positive cells drug resistant and accelerates tumor growth. Molecular Cancer Research, 12(3), 408-420. https://doi.org/10.1158/1541-7786.MCR-13-0206-T