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. IκB 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.

胰腺导管腺癌 (PDAC) 是一种致命疾病，总体中位 5 年生存率为 8%。这种不良的预后是由于对化疗和放疗产生耐药性以及缺乏有效的靶向治疗。IκB 激酶增强子 (IKBKE) 过度表达先前被认为与化疗耐药有关。由于 IKBKE 在 PDAC 中经常升高，并且 IKBKE 抑制剂目前正在进行临床试验，因此我们评估了 IKBKE 作为该疾病的治疗靶点。研究发现，IKBKE 的缺失会显着降低 PDAC 细胞的存活、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 CYT387 和 IKBKE 敲低显着激活了 MAPK 通路。Phospho-RTK 阵列分析表明，IKBKE 抑制会导致 ErbB3 和 IGF-1R 表达快速上调，从而导致 MAPK-ERK 通路激活，从而限制 IKBKE 抑制剂的功效。此外，IKBKE 抑制导致 FOXO3a 稳定，这是 RTK 上调 IKBKE 抑制所必需的。最后，我们证明 IKBKE 抑制剂与 MEK 抑制剂曲美替尼 (Trametinib) 协同作用，可在原位 PDAC 小鼠模型中显着诱导细胞死亡并抑制肿瘤生长和肝转移。