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Mol Cancer Res. 2014 Mar;12(3):408-420. doi: 10.1158/1541-7786.MCR-13-0206-T. Epub 2013 Dec 6.

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

Author information

1
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02115.
2
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
3
Department of Cancer Biology, Dana-Farber Cancer Institute & Harvard Medical School. Boston, MA 02115.
4
Department of Pathology, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115.
5
Department of Surgery, Brigham & Women's Hospital and Harvard Medical School. Boston, MA 02115.
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Contributed equally

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 IκB kinase (IKK) inhibitor and anti-HER2 drugs may be a novel treatment strategy for drug-resistant human breast cancers.

PMID:
24319068
PMCID:
PMC4026253
DOI:
10.1158/1541-7786.MCR-13-0206-T
[Indexed for MEDLINE]
Free PMC Article
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