Rajurkar Mihir, Dang Kyvan, Fernandez-Barrena Maite G, Liu Xiangfan, Fernandez-Zapico Martin E, Lewis Brian C, Mao Junhao
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts.
Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, Minnesota.
Cancer Res. 2017 Jan 15;77(2):320-329. doi: 10.1158/0008-5472.CAN-15-1684. Epub 2017 Jan 9.
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies lacking effective therapeutic strategies. Here, we show that the noncanonical IκB-related kinase, IKBKE, is a critical oncogenic effector during KRAS-induced pancreatic transformation. Loss of IKBKE inhibits the initiation and progression of pancreatic tumors in mice carrying pancreatic-specific KRAS activation. Mechanistically, we demonstrate that this protumoral effect of IKBKE involves the activation of GLI1 and AKT signaling and is independent of the levels of activity of the NF-κB pathway. Further analysis reveals that IKBKE regulates GLI1 nuclear translocation and promotes the reactivation of AKT post-inhibition of mTOR in PDAC cells. Interestingly, combined inhibition of IKBKE and mTOR synergistically blocks pancreatic tumor growth. Together, our findings highlight the functional importance of IKBKE in pancreatic cancer, support the evaluation of IKBKE as a therapeutic target in PDAC, and suggest IKBKE inhibition as a strategy to improve efficacy of mTOR inhibitors in the clinic. Cancer Res; 77(2); 320-9. ©2017 AACR.
胰腺导管腺癌（PDAC）是最致命的恶性肿瘤之一，缺乏有效的治疗策略。在此，我们表明非经典IκB相关激酶IKBKE是KRAS诱导的胰腺转化过程中的关键致癌效应因子。IKBKE的缺失抑制了携带胰腺特异性KRAS激活的小鼠胰腺肿瘤的起始和进展。从机制上讲，我们证明IKBKE的这种促肿瘤作用涉及GLI1和AKT信号通路的激活，且独立于NF-κB通路的活性水平。进一步分析表明，IKBKE调节PDAC细胞中GLI1的核转位，并在mTOR抑制后促进AKT的重新激活。有趣的是，联合抑制IKBKE和mTOR可协同阻断胰腺肿瘤生长。总之，我们的研究结果突出了IKBKE在胰腺癌中的功能重要性，支持将IKBKE评估为PDAC的治疗靶点，并表明抑制IKBKE是提高mTOR抑制剂临床疗效的一种策略。《癌症研究》；77(2)；320 - 329。©2017美国癌症研究协会。
