Bailey Shannon T, Miron Penelope L, Choi Yoon J, Kochupurakkal Bose, Maulik Gautam, Rodig Scott J, Tian Ruiyang, Foley Kathleen M, Bowman Teresa, Miron Alexander, Brown Myles, Iglehart J Dirk, Debajit K Biswas
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02115.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
Mol Cancer Res. 2014 Mar;12(3):408-420. doi: 10.1158/1541-7786.MCR-13-0206-T. Epub 2013 Dec 6.
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.
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.
HER2过表达的乳腺癌对靶向该受体或其激酶活性的药物敏感。HER2靶向药物最初对HER2阳性乳腺癌有效，但不可避免地会出现耐药性。我们之前发现NF-κB在一部分HER2阳性乳腺癌细胞和组织标本中过度激活。在本研究中，我们报告持续激活的NF-κB使HER2阳性癌细胞对抗HER2药物产生耐药性，而选择对拉帕替尼耐药的细胞会上调NF-κB。在这两种情况下，细胞都具有抗凋亡能力，并且作为异种移植物快速生长。对拉帕替尼耐药的细胞单独对HER2和NF-κB抑制剂均无反应，但对它们的联合使用敏感，这提示了一种新的治疗策略。一部分NF-κB反应性基因在HER2阳性和三阴性乳腺癌中过表达，具有这种NF-κB特征的患者临床预后较差。抗HER2药物耐药可能是NF-κB激活的结果，而耐药性选择导致NF-κB激活，这表明该转录因子在肿瘤发生和耐药中起核心作用。临床上，联合靶向HER2和NF-κB为抗HER2治疗后复发的患者提示了一种潜在的治疗模式。这些癌症患者可通过同时抑制HER2信号传导和NF-κB激活来治疗。
IκB激酶（IKK）抑制剂与抗HER2药物联合使用可能是耐药性人类乳腺癌的一种新治疗策略。
