IKBKE is required during KRAS-induced pancreatic tumorigenesis

Mihir Rajurkar, Kyvan Dang, Maite G. Fernandez-Barrena, Xiangfan Liu, Martin E. Fernandez-Zapico, Brian C. Lewis, Junhao Mao

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)320-329
Number of pages10
JournalCancer research
Volume77
Issue number2
DOIs
StatePublished - Jan 15 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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