Format

Send to

Choose Destination
Cancer Res. 2017 Jan 15;77(2):320-329. doi: 10.1158/0008-5472.CAN-15-1684. Epub 2017 Jan 9.

IKBKE Is Required during KRAS-Induced Pancreatic Tumorigenesis.

Author information

1
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts.
2
Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, Minnesota.
3
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts. junhao.mao@umassmed.edu.

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. Cancer Res; 77(2); 320-9.

PMID:
28069799
PMCID:
PMC5243176
DOI:
10.1158/0008-5472.CAN-15-1684
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center