Targeting the IκB Kinase Enhancer and Its Feedback Circuit in Pancreatic Cancer
Targeting the IκB Kinase Enhancer and Its Feedback Circuit in Pancreatic Cancer
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DOI：
10.1016/j.tranon.2019.11.009
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发表时间：
2020-02-01
影响因子：
5
通讯作者：
Malafa, Mokenge P.
中科院分区：
文献类型：
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作者：
Challa, Sridevi;Husain, Kazim;Malafa, Mokenge P.
胰腺导管腺癌（PDAC）是一种致命的疾病，总的中位5年生存率为8%。这种不良预后是由于对化疗和放射治疗的耐药性以及缺乏有效的靶向治疗。I κ B激酶增强子（IKBKE）的过度表达与化疗耐药有关。由于IKBKE在PDAC中经常升高，并且IKBKE抑制剂目前正在临床试验中，因此我们评估了IKBKE作为这种疾病的治疗靶点。发现IKBKE的耗尽显著降低PDAC细胞存活、生长、癌症干细胞更新以及细胞迁移和侵袭。值得注意的是，IKBKE抑制剂CYT 387和IKBKE敲低显著激活MAPK通路。磷酸-RTK阵列分析表明，IKBKE抑制导致ErbB 3和IGF-1 R表达的快速上调，这导致MAPK-ERK通路激活，从而限制了IKBKE抑制剂的疗效。此外，IKBKE抑制导致FOXO 3a的稳定，这是IKBKE抑制时RTK上调所需的。最后，我们证明了IKBKE抑制剂与MEK抑制剂曲美替尼协同作用，在原位PDAC小鼠模型中显著诱导细胞死亡并抑制肿瘤生长和肝转移。
Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with an overall median 5-year survival rate of 8%. This poor prognosis is because of the development of resistance to chemotherapy and radiation therapy and lack of effective targeted therapies. I kappa B kinase enhancer (IKBKE) overexpression was previously implicated in chemoresistance. Because IKBKE is frequently elevated in PDAC and IKBKE inhibitors are currently in clinical trials, we evaluated IKBKE as a therapeutic target in this disease. Depletion of IKBKE was found to significantly reduce PDAC cell survival, growth, cancer stem cell renewal, and cell migration and invasion. Notably, IKBKE inhibitor CYT387 and IKBKE knockdown dramatically activated the MAPK pathway. Phospho-RTK array analyses showed that IKBKE inhibition leads to rapid upregulation of ErbB3 and IGF-1R expression, which results in MAPK-ERK pathway activation-thereby limiting the efficacy of IKBKE inhibitors. Furthermore, IKBKE inhibition leads to stabilization of FOXO3a, which is required for RTK upregulation on IKBKE inhibition. Finally, we demonstrated that the IKBKE inhibitors synergize with the MEK inhibitor trametinib to significantly induce cell death and inhibit tumor growth and liver metastasis in an orthotopic PDAC mouse model.