TY - JOUR
T1 - IKBKE is required during KRAS-induced pancreatic tumorigenesis
AU - Rajurkar, Mihir
AU - Dang, Kyvan
AU - Fernandez-Barrena, Maite G.
AU - Liu, Xiangfan
AU - Fernandez-Zapico, Martin E.
AU - Lewis, Brian C.
AU - Mao, Junhao
N1 - Funding Information:
We thank members of Mao, Lewis, and Fernandez-Zapico laboratories for helpful discussion. J. Mao is supported by NIH grant R01DK099510 and American Cancer Society grant RSG-11-040-01-DDC. M.E. Fernandez-Zapico is supported by NIH grant R01CA136526. B.C. Lewis is supported by grant R01CA155784. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
©2017 AACR.
PY - 2017/1/15
Y1 - 2017/1/15
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-15-1684
DO - 10.1158/0008-5472.CAN-15-1684
M3 - Article
C2 - 28069799
AN - SCOPUS:85018658029
SN - 0008-5472
VL - 77
SP - 320
EP - 329
JO - Cancer Research
JF - Cancer Research
IS - 2
ER -