Challa Sridevi, Husain Kazim, Kim Richard, Coppola Domenico, Batra Surinder K, Cheng Jin Q, Malafa Mokenge P
Departments of Molecular Oncology, Tampa, FL, USA.
Gastrointestinal Oncology, Tampa, FL, USA.
Transl Oncol. 2020 Feb;13(2):481-489. doi: 10.1016/j.tranon.2019.11.009. Epub 2020 Jan 28.
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%。这种预后不良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）过表达先前被认为与化疗耐药有关。由于IKBKE在PDAC中经常升高且IKBKE抑制剂目前正在进行临床试验，我们评估了IKBKE作为这种疾病的治疗靶点。发现IKBKE的缺失可显著降低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基因敲低显著激活了MAPK通路。磷酸化RTK阵列分析表明，IKBKE抑制导致ErbB3和IGF-1R表达迅速上调，从而导致MAPK-ERK通路激活，进而限制了IKBKE抑制剂的疗效。此外，IKBKE抑制导致FOXO3a稳定，这是IKBKE抑制后RTK上调所必需的。最后，我们证明IKBKE抑制剂与MEK抑制剂曲美替尼协同作用，可在原位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。
