Ebelt Nancy D, Kaoud Tamer S, Edupuganti Ramakrishna, Van Ravenstein Sabrina, Dalby Kevin N, Van Den Berg Carla L
Institute of Cellular & Molecular Biology, University of Texas at Austin, Dell Pediatric Research Institute, Austin, TX 78723, USA.
Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy, University of Texas at Austin, Austin, TX 78712, USA.
Oncotarget. 2017 Aug 24;8(62):104894-104912. doi: 10.18632/oncotarget.20581. eCollection 2017 Dec 1.
Triple negative breast cancers (TNBC) have poor prognosis compared to other breast cancer subtypes and represent 15-20% of breast cancers diagnosed. Unique targets and new molecularly-targeted therapies are urgently needed for this subtype. Despite high expression of Epidermal Growth Factor Receptor, inhibitors such as lapatinib have not shown therapeutic efficacy in TNBC patients. Herein, we report that treatment with the covalent JNK inhibitor, JNK-IN-8, synergizes with lapatinib to cause cell death, while these compounds as single agents have little effect. The combination significantly increases survival of mice bearing xenografts of MDA-MB-231 human TNBC cells. Our studies demonstrate that lapatinib treatment increases c-Jun and JNK phosphorylation indicating a mechanism of resistance. Combined, these compounds significantly reduce transcriptional activity of Nuclear Factor kappa B, Activating Protein 1, and Nuclear factor erythroid 2-Related Factor 2. As master regulators of antioxidant response, their decreased activity induces a 10-fold increase in reactive oxygen species that is cytotoxic, and is rescued by addition of exogenous antioxidants. Over expression of p65 or Nrf2 also significantly rescues viability during JNK-IN-8 and lapatinib treatment. Further studies combining JNK-IN-8 and lapatinib may reveal a benefit for patients with TNBC, fulfilling a critical medical need.
与其他乳腺癌亚型相比，三阴性乳腺癌（TNBC）的预后较差，占确诊乳腺癌的15%-20%。该亚型迫切需要独特的靶点和新的分子靶向疗法。尽管表皮生长因子受体表达较高，但拉帕替尼等抑制剂在TNBC患者中并未显示出治疗效果。在此，我们报告，共价JNK抑制剂JNK-IN-8与拉帕替尼联合治疗可协同导致细胞死亡，而这些化合物单独使用时几乎没有效果。该联合用药显著提高了携带MDA-MB-231人TNBC细胞异种移植瘤小鼠的存活率。我们的研究表明，拉帕替尼治疗会增加c-Jun和JNK磷酸化，这表明了一种耐药机制。综合来看，这些化合物显著降低了核因子κB、活化蛋白1和核因子红细胞2相关因子2的转录活性。作为抗氧化反应的主要调节因子，它们活性的降低会导致细胞毒性的活性氧增加10倍，而添加外源性抗氧化剂可使其恢复。p65或Nrf2的过表达在JNK-IN-8和拉帕替尼治疗期间也显著挽救了细胞活力。进一步研究JNK-IN-8与拉帕替尼的联合使用可能会给TNBC患者带来益处，满足一项关键的医疗需求。
