Related Experiment Video
Updated: Apr 27, 2026
Endobronchial Ultrasound-guided Intratumoral Injection of Cisplatin for the Treatment of Isolated Mediastinal Recurrence of Lung Cancer
Published on: February 12, 2017
Strategic targeting of the PI3K-NFκB axis in cisplatin-resistant NSCLC
Susan Heavey1, Peter Godwin1, Anne-Marie Baird2
1Thoracic Oncology Research Group; Institute of Molecular Medicine; Trinity Centre for Health Sciences; St. James's Hospital; Dublin, Ireland.
Abstract:
Chemoresistance is a major therapeutic challenge to overcome in NSCLC, in order to improve the current survival rates of<15% at 5 years. We and others have shown increased PI3K signaling in NSCLC to be associated with a more aggressive disease, and a poorer prognosis. In this study, targeted inhibition of three strategic points of the PI3K-NFκB axis was performed with the aim of exploiting vulnerabilities in cisplatin-resistant NSCLC cells. Cisplatin-resistant cell lines were previously generated through prolonged exposure to the drug. Expression of PI3K and NFκB pathway-related genes were compared between cisplatin-resistant cells and their matched parent cells using a gene expression array, qRT-PCR, DNA sequencing, western blot, and immunofluorescence. Targeted inhibition was performed using GDC-0980, a dual PI3K-mTOR inhibitor currently in Phase II clinical trials in NSCLC, and DHMEQ, an inhibitor of NFκB translocation which has been used extensively both in vitro and in vivo. Effects of the two inhibitors were assessed by BrdU proliferation assay and multiparameter viability assay. NFKBIA was shown to be 12-fold overexpressed in cisplatin-resistant cells, with no mutations present in exons 3, 4, or 5 of the gene. Corresponding overexpression of IκBα was also observed. Treatment with DHMEQ (but not GDC-0980) led to significantly enhanced effects on viability and proliferation in cisplatin-resistant cells compared with parent cells. We conclude that NFκB inhibition represents a more promising strategy than PI3K-mTOR inhibition for treatment in the chemoresistance setting in NSCLC.
Insights
Nuclear factor-kappa B (NFκB) inhibition shows promise for overcoming chemoresistance in non-small cell lung cancer (NSCLC). Targeting NFκB, not PI3K-mTOR, significantly enhanced treatment effects in cisplatin-resistant NSCLC cells.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Chemoresistance in non-small cell lung cancer (NSCLC) significantly limits treatment efficacy, contributing to poor patient survival rates.
- Increased phosphoinositide 3-kinase (PI3K) signaling is linked to aggressive NSCLC and worse prognosis.
- Understanding resistance mechanisms is crucial for developing effective therapeutic strategies.
Purpose of the Study:
- To investigate the therapeutic potential of targeting the PI3K-NFκB axis in cisplatin-resistant NSCLC.
- To identify vulnerabilities in chemoresistant NSCLC cells by comparing gene expression profiles.
- To evaluate the efficacy of dual PI3K-mTOR inhibitor (GDC-0980) and NFκB translocation inhibitor (DHMEQ) in resistant cells.
Main Methods:
- Generated cisplatin-resistant NSCLC cell lines through prolonged drug exposure.
- Compared gene expression of PI3K and NFκB pathway-related genes using gene arrays, qRT-PCR, DNA sequencing, western blot, and immunofluorescence.
- Assessed inhibitor effects on cell proliferation and viability using BrdU assay and multiparameter viability assay.
Main Results:
- NFKBIA was overexpressed 12-fold in cisplatin-resistant cells without mutations in key exons.
- Corresponding overexpression of IκBα was observed in resistant cells.
- DHMEQ treatment significantly enhanced anti-proliferative and viability effects in resistant cells, whereas GDC-0980 showed no significant difference compared to parent cells.
Conclusions:
- NFκB pathway dysregulation, specifically NFKBIA overexpression, is implicated in cisplatin resistance in NSCLC.
- Targeted inhibition of NFκB translocation with DHMEQ is a more promising strategy than PI3K-mTOR inhibition for overcoming chemoresistance in NSCLC.
- Further research into NFκB as a therapeutic target could improve treatment outcomes for chemoresistant NSCLC.
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...