NF-kB Activation-Induced Anti-apoptosis Renders HER2- Positive Cells Drug Resistant and Accelerates Tumor Growth

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-kB is hyperactivated in a subset of HER2-positive breast cancer cells and tissue specimens. In this study, we report that constitutively active NF-kB rendered HER2-positive cancer cells resistant to anti-HER2 drugs and cells selected for lapatinib resistance upregulatedNF-kB. In both circumstances, cells were antiapoptotic and grew rapidly as xenografts. Lapatinib-resistant cells were refractory to HER2 and NF-kB inhibitors alone but were sensitive to their combination, suggesting a novel therapeutic strategy. A subset of NFkB–responsive genes was overexpressed in HER2-positive and triple-negative breast cancers, and patients with this NF-kB signature had poor clinical outcome. Anti-HER2 drug resistance may be a consequence of NF-kB activation, and selection for resistance results inNF-kB activation, suggesting that this transcription factor is central to oncogenesis and drug resistance. Clinically, the combined targeting of HER2 and NF-kB 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-kB activation. Implications:The combination of an inhibitor of IkB kinase (IKK) inhibitor and anti-HER2 drugsmay be a novel treatment strategy for drug-resistant human breast cancers. Mol Cancer Res; 12(3); 408–20. 2013 AACR.