NF-κB 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 toanti-HER2drugsandcellsselectedforlapatinibresistanceupregulatedNF-kB.Inbothcircumstances,cellswere 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 inHER2-positive and triple-negative breast cancers, and patients withthis NF-kB signature had poor clinical outcome. Anti-HER2 drug resistance may be a consequence of NF-kB activation,andselectionforresistanceresultsinNF-kBactivation,suggestingthatthistranscriptionfactoriscentral to oncogenesis and drug resistance. Clinically, the combined targeting of HER2 and NF-kB suggests a potential treatmentparadigmforpatientswhorelapseafteranti-HER2therapy.Patientswiththesecancersmaybetreatedby simultaneously suppressing HER2 signaling and NF-kB activation. Implications:ThecombinationofaninhibitorofIkBkinase(IKK)inhibitorandanti-HER2drugsmaybeanovel treatment strategy for drug-resistant human breast cancers. Mol Cancer Res; 12(3); 408–20. � 2013 AACR.