Co-Targeting of JNK and HUNK in Resistant HER2-Positive Breast Cancer.
Co-Targeting of JNK and HUNK in Resistant HER2-Positive Breast Cancer.
复制标题
JNK和Hunk在耐药的HER2阳性乳腺癌中共同推荐。
DOI：
10.1371/journal.pone.0153025
复制
发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Yeh ES
中科院分区：
文献类型：
--
作者：
Phelps-Polirer K;Abt MA;Smith D;Yeh ES
成功治疗HER2阳性乳腺癌的策略包括使用HER2抑制剂曲妥珠单抗或拉帕替尼联合标准化疗。虽然取得了成功，但许多患者对这些HER2抑制剂产生了耐药性，这表明需求未得到满足。因此，目前的研究工作是为了了解抗性的机制和调节这些机制的信号模式。我们进行了一项研究，以检查表皮生长因子受体下游的信号分子是否可以共同靶向克服耐药性，这些信号分子通常作为代偿性信号通路来规避HER2抑制。我们确定JNK信号是一个潜在的干预领域，现在表明使用泛JNK抑制剂SP600125抑制JNK，在her2阳性，耐药的JIMT-1异种移植乳腺肿瘤模型中有效。我们还研究了潜在的联合策略来增强JNK抑制的效果，并发现JNK和蛋白激酶HUNK的共同靶向可以在体内阻止耐药her2阳性乳腺肿瘤的肿瘤生长。
Strategies for successful primary treatment of HER2-positive breast cancer include use of the HER2 inhibitors trastuzumab or lapatinib in combination with standard chemotherapy. While successful, many patients develop resistance to these HER2 inhibitors indicating an unmet need. Consequently, current research efforts are geared toward understanding mechanisms of resistance and the signaling modalities that regulate these mechanisms. We have undertaken a study to examine whether signaling molecules downstream of epidermal growth factor receptor, which often act as compensatory signaling outlets to circumvent HER2 inhibition, can be co-targeted to overcome resistance. We identified JNK signaling as a potential area of intervention and now show that inhibiting JNK using the pan-JNK inhibitor, SP600125, is effective in the HER2-positive, resistant JIMT-1 xenograft mammary tumor model. We also investigate potential combination strategies to bolster the effects of JNK inhibition and find that co-targeting of JNK and the protein kinase HUNK can prohibit tumor growth of resistant HER2-positive mammary tumors in vivo.