Related Experiment Video
Updated: Dec 29, 2025
Author Spotlight: Reprogramming Cancer Cells to iPSCs to Study Disease Progression and Treatment Targets
Published on: February 2, 2024
Targeting the IκB Kinase Enhancer and Its Feedback Circuit in Pancreatic Cancer
Sridevi Challa1, Kazim Husain2, Richard Kim2
1Departments of Molecular Oncology, Tampa, FL, USA.
Abstract:
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.
Insights
Targeting IκB kinase enhancer (IKBKE) shows promise for pancreatic cancer. Inhibiting IKBKE and MEK simultaneously overcomes resistance, significantly reducing tumor growth and metastasis in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis due to treatment resistance and lack of targeted therapies.
- Overexpression of IκB kinase enhancer (IKBKE) is linked to chemoresistance in PDAC.
- IKBKE inhibitors are under clinical investigation, prompting evaluation as a therapeutic target.
Purpose of the Study:
- To evaluate IKBKE as a therapeutic target in pancreatic ductal adenocarcinoma.
- To investigate the mechanisms underlying IKBKE inhibitor efficacy and resistance.
- To explore combination therapies for enhanced PDAC treatment.
Main Methods:
- Depletion of IKBKE using knockdown techniques.
- Treatment with IKBKE inhibitor CYT387 and MEK inhibitor trametinib.
- Analysis of cell survival, growth, stem cell renewal, migration, invasion, MAPK pathway activation, RTK expression, and FOXO3a stabilization.
- Evaluation in an orthotopic PDAC mouse model.
Main Results:
- IKBKE depletion reduced PDAC cell survival, growth, stem cell renewal, migration, and invasion.
- IKBKE inhibition activated the MAPK pathway via upregulation of ErbB3 and IGF-1R, limiting inhibitor efficacy.
- IKBKE inhibition stabilized FOXO3a, contributing to RTK upregulation.
- Combination of IKBKE and MEK inhibitors synergistically induced cell death and inhibited tumor growth and liver metastasis in mice.
Conclusions:
- IKBKE is a viable therapeutic target for PDAC, with its inhibition impacting critical cancer cell functions.
- Upregulation of RTKs and MAPK pathway activation represent resistance mechanisms to IKBKE inhibitors.
- Combining IKBKE inhibitors with MEK inhibitors, such as trametinib, offers a synergistic approach to overcome resistance and improve PDAC treatment outcomes.
Related Concept Videos
01:22PI3K/mTOR/AKT Signaling Pathway
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...
01:19Interactions Between Signaling Pathways
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...