A c-Jun N-terminal kinase inhibitor, JNK-IN-8, sensitizes triple negative breast cancer cells to lapatinib.
A c-Jun N-terminal kinase inhibitor, JNK-IN-8, sensitizes triple negative breast cancer cells to lapatinib.
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DOI：
10.18632/oncotarget.20581
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发表时间：
2017-12-01
期刊：
影响因子：
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通讯作者：
Van Den Berg CL
中科院分区：
文献类型：
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作者：
Ebelt ND;Kaoud TS;Edupuganti R;Van Ravenstein S;Dalby KN;Van Den Berg CL
与其他乳腺癌亚型相比，三阴性乳腺癌(TNBC)预后较差，占确诊乳腺癌的15-20%。这一亚型迫切需要独特的靶点和新的分子靶向治疗方法。尽管表皮生长因子受体高表达，但拉帕替尼等抑制剂对TNBC患者并未显示出疗效。在这里，我们报告了共价JNK抑制剂JNK-IN-8与拉帕替尼协同治疗导致细胞死亡，而这些化合物作为单一药物几乎没有作用。联合用药显著提高了移植有MDA-MB-231人TNBC细胞的小鼠的存活率。我们的研究表明，拉帕替尼治疗增加了c-jun和JNK的磷酸化，这表明了一种耐药机制。这些化合物结合在一起，显著降低核因子kappa B、激活蛋白1和核因子红系相关因子2的转录活性。作为抗氧化反应的主要调节因子，它们的活性降低导致具有细胞毒性的活性氧物种增加10倍，并通过添加外源抗氧化剂来挽救。在JNK-IN-8和拉帕替尼治疗期间，p65或Nrf2的过表达也显著挽救了生存能力。结合JNK-IN-8和拉帕替尼的进一步研究可能会显示出对TNBC患者的好处，满足了关键的医疗需求。
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.